Substituted dihydrobenzofuran glycosidase inhibitors

ABSTRACT

Compounds of formula (I), wherein R′, R″, R, X, W, Q, n, and m have the meaning according to the claims, can be employed, inter alia, for the treatment of tauopathies and Alzheimer&#39;s disease.

The present invention relates to a medicament comprising a compound offormula (I)

wherein R, R′, R″, X, W, Q, n and m have the meaning according to theclaims, and/or physiologically acceptable salts, tautomers, solvates,stereoisomers and derivatives thereof. The compounds of formula (I) canbe used as glycosidase inhibitors. Objects of the invention are alsopharmaceutical compositions comprising the compounds of formula (I), andthe use of the compounds of formula (I) for the treatment of one or moretauopathies and Alzheimer's disease.

A wide range of cellular proteins, both nuclear and cytoplasmic, arepost-translationally modified by the addition of the monosaccharide2-acetamido-2-deoxy-β-D-glucopyranoside (β-N-acetyl glucosamine) whichis attached via an O-glycosidic linkage. This modification is generallyreferred to as O-linked N-acetylglucosamine or O-GlcNAc. The enzymeresponsible for post-translationally linking β-N-acetylglucosamine(GlcNAc) to specific serine and threonine residues of numerousnucleocytoplasmic proteins is O-GlcNAc transferase (OGTase). A secondenzyme, known as O-GlcNAcase, removes this post-translationalmodification to liberate proteins making the O-GlcNAc-modification adynamic cycle occurring several times during the lifetime of a protein.

O-GlcNAc-modified proteins regulate a wide range of vital cellularfunctions including, for example, transcription, proteasomal degradationand cellular signaling. O-GlcNAc is also found on many structuralproteins. For example, it has been found on a number of cytoskeletalproteins, including neurofilament proteins, synapsins, synapsin-specificclathrin assembly protein AP-3 and Ankyrin-G. O-GlcNAc modification hasbeen found to be abundant in the brain. It has also been found onproteins clearly implicated in the etiology of several diseasesincluding tauopathies, Alzheimer's disease (AD), synucleinopathies,Parkinson's disease, amyotrophic lateral sclerosis, and cancer.

For example, it is well established that AD and a number of relatedtauopathies including Down's Syndrome, progressive supranuclear palsy(PSP), Pick's disease, corticobasal degeneration (CBD), argyrophilicgrain disease (AGD), globular glial tauopathy (GGT), frontotemporaldementia and parkinsonism linked to chromosome-17 (FTLD-17, Niemann-PickType C disease are characterized, in part, by the development ofneurofibrillary tangles (NFTs). NFTs are also a histopathologicalhallmark of chronic traumatic encephalopathy that is a consequence oftraumatic brain injury. These NFTs are aggregates of paired helicalfilaments (PHFs) and are composed of an abnormal form of thecytoskeletal protein “tau”. Normally, tau stabilizes a key cellularnetwork of microtubules that is essential for distributing proteins andnutrients within neurons. In AD patients, however, tau becomeshyperphosphorylated, disrupting its normal function, forming PHFs andultimately aggregating to form NFTs. Six isoforms of tau are found inthe human brain. In AD patients, all six isoforms of tau are found inNFTs, and all are markedly hyperphosphorylated. Tau in healthy braintissue bears only 2 or 3 phosphate groups, whereas those found in thebrains of AD patients bear, on average, 8 phosphate groups. A clearparallel between NFT levels in the brains of AD patients and theseverity of dementia strongly supports a key role for tau dysfunction inAD. The precise causes of this hyperphosphorylation of tau remainelusive. Accordingly, considerable effort has been dedicated toward: a)elucidating the molecular physiological basis of tauhyperphosphorylation; and b) identifying strategies that could limit tauhyperphosphorylation in the hope that these might halt, or even reverse,the progression of tauopathies and Alzheimer's disease. Several lines ofevidence suggest that up-regulation of a number of kinases may beinvolved in hyperphosphorylation of tau, although very recently, analternative basis for this hyperphosphorylation has been advanced.

In particular, it has recently emerged that phosphate levels of tau areregulated by the levels of O-GlcNAc on tau. The presence of O-GlcNAc ontau has stimulated studies that correlate O-GlcNAc levels with tauphosphorylation levels. The recent interest in this field stems from theobservation that O-GlcNAc modification has been found to occur on manyproteins at amino acid residues that are also known to bephosphorylated. Consistent with this observation, it has been found thatincreases in phosphorylation levels result in decreased O-GlcNAc levelsand conversely, increased O-GlcNAc levels correlate with decreasedphosphorylation levels. This reciprocal relationship between O-GlcNAcand phosphorylation has been termed the “Yin-Yang hypothesis” and hasgained strong biochemical support by the recent discovery that theenzyme OGTase forms a functional complex with phosphatases that act toremove phosphate groups from proteins. Like phosphorylation, O-GlcNAc isa dynamic modification that can be removed and reinstalled several timesduring the lifespan of a protein. Suggestively, the gene encodingO-GlcNAcase has been mapped to a chromosomal locus that is linked to AD.Hyperphosphorylated tau in human AD brains has markedly lower levels ofO-GlcNAc than are found in healthy human brains. Very recently, it hasbeen shown that O-GlcNAc levels of soluble tau protein from human brainsaffected with AD are markedly lower than those from healthy brain.Furthermore, PHF from diseased brain was suggested to lack completelyany O-GlcNAc modification whatsoever. The molecular basis of thishypoglycosylation of tau is not known, although it may stem fromincreased activity of kinases and/or dysfunction of one of the enzymesinvolved in processing O-GlcNAc. Supporting this latter view, in bothPC-12 neuronal cells and in brain tissue sections from mice, anonselective N-acetylglucosaminidase inhibitor was used to increase tauO-GlcNAc levels, whereupon it was observed that phosphorylation levelsdecreased. Moreover, it has been described that the O-GlcNAcmodification of tau directly inhibits its aggregation without perturbingthe conformational properties of tau monomers. The implication of thesecollective results is that by maintaining healthy O-GlcNAc levels in ADpatients, such as by inhibiting the action of O-GlcNAcase (OGA), oneshould be able to block hyperphosphorylation of tau and all of theassociated effects of tau hyperphosphorylation, including the formationof NFTs and downstream effects. However, because the proper functioningof the lysosomal β-hexosaminidases is critical, any potentialtherapeutic intervention for the treatment of AD that blocks the actionof O-GlcNAcase would have to avoid the concomitant inhibition of bothlysosomal hexosaminidases A and B.

Consistent with the known properties of the hexosamine biosyntheticpathway, the enzymatic properties of O-GlcNAc transferase (OGTase), andthe reciprocal relationship between O-GlcNAc and phosphorylation, it hasbeen shown that decreased glucose availability in brain leads to tauhyperphosphorylation. The gradual impairment of glucose transport andmetabolism leads to decreased O-GlcNAc and hyperphosphorylation of tau(and other proteins). Accordingly, the inhibition of O-GlcNAcase shouldcompensate for the age-related impairment of glucose metabolism withinthe brains of health individuals as well as patients suffering from ADor related neurodegenerative diseases.

These results suggest that a malfunction in the mechanisms regulatingtau O-GlcNAc levels may be vitally important in the formation of NFTsand associated neurodegeneration. Good support for blocking tauhyperphosphorylation as a therapeutically useful intervention comes fromstudies showing that when transgenic mice harboring human tau aretreated with kinase inhibitors, they do not develop typical motordefects and, in another case, show a decreased level of insoluble tau.

These studies provide a clear link between lowering tau phosphorylationlevels and alleviating AD-like behavioral symptoms in a murine model ofthis disease.

There is evidence indicating that the modification with O-GlcNAc mayhave a general function in preventing harmful protein aggregation. Thishas been directly demonstrated for the tau protein and also for theprotein alpha-synuclein that is a toxic aggregating protein associatedwith synucleinopathies, including Parkinson's disease. Two otheraggregating proteins that are associated with amyotrophic lateralysclerosis (Tar DNA binding protein-43 (TDP-43) and superoxide-dismutaseI (SOD-I)) and frontotemporal lobar degeneration (TDP-43) are known tocarry the O-GlcNAc modification. These results indicate that increasingO-GlcNAcylation with OGA inhibitors could be in general beneficial indiseases associated with protein aggregation.

There is also a large body of evidence indicating that increased levelsof O-GlcNAc protein modification provides protection against pathogeniceffects of stress in cardiac tissue, including stress caused byischemia, hemorrhage, hypervolemic shock, and calcium paradox. Forexample, activation of the hexosamine biosynthetic pathway (HBP) byadministration of glucosamine has been demonstrated to exert aprotective effect in animal models of ischemia/reperfusion, traumahemorrhage, hypervolemic shock and calcium paradox. Moreover, strongevidence indicates that these cardioprotective effects are mediated byelevated levels of protein O-GlcNAc modification. There is also evidencethat the O-GlcNAc modification plays a role in a variety ofneurodegenerative diseases, including Parkinson's disease and relatedsynucleinopathies, and Huntington's disease.

Humans have three genes encoding enzymes that cleave terminalβ-N-acetyl-glucosamine residues from glycoconjugates. The first of theseencodes the enzymeO-glycoprotein-2-acetamido-2-deoxy-β-D-glucopyranosidase (O-GlcNAcase).O-GlcNAcase is a member of family 84 of glycoside hydrolases.O-GlcNAcase acts to hydrolyze O-GlcNAc off of serine and threonineresidues of post-translationally modified proteins. Consistent with thepresence of O-GlcNAc on many intracellular proteins, the enzymeO-GlcNAcase appears to have a role in the etiology of several diseasesincluding type II diabetes, AD and cancer. Although O-GlcNAcase waslikely isolated earlier on, about 20 years elapsed before itsbiochemical role in acting to cleave O-GlcNAc from serine and threonineresidues of proteins was understood. More recently O-GlcNAcase has beencloned, partially characterized, and suggested to have additionalactivity as a histone acetyltra nsferase.

However, a major challenge in developing inhibitors for blocking thefunction of mammalian glycosidases, including O-GlcNAcase, is the largenumber of functionally related enzymes present in tissues of highereukaryotes. Accordingly, the use of non-selective inhibitors in studyingthe cellular and organismal physiological role of one particular enzymeis complicated because complex phenotypes arise from the concomitantinhibition of such functionally related enzymes. In the case ofβ-N-acetylglucosaminidases, existing compounds that act to blockO-GlcNAcase function are non-specific and act potently to inhibit thelysosomal 1-hexosaminidases.

Low molecular weight OGA inhibitors are e.g. disclosed in theinternational applications WO 2008/025170 and WO 2014/032187, which arestructurally different from the compounds of the present invention.Further compounds that have some structurally similar elements aredisclosed in WO 2016/030443, U.S. Pat. Nos. 3,489,757, 3,299,067, WO99/21850, WO 2005/110982 and WO 2009/053373. However, these compounds donot show the improved pharmacological properties more closely describedbelow.

Presently, no OGA inhibitor has reached the market. Thus, there is aneed for low molecular weight molecules that selectively inhibit OGA andprovide improved pharmacological properties that are of high relevancein drug development.

The present invention has the object of providing novel compounds havingvaluable properties, in particular those which can be used for thepreparation of medicaments.

In this regard, plasma protein binding (PPB) is an importantdifferentiating factor in drug development as it determines at least inpart the unbound, and thus, likely effective) drug concentrations atpharmacological target site. It is a well-acknowledged paradigm that, inthe absence of energy-dependent processes (e.g. transporter-mediatedactive organ uptake or efflux), once steady state equilibrium has beenreached, unbound drug concentration in plasma may be considered equal tounbound drug concentration in the target tissue(s), i.e. only theunbound drug in the tissues is available for binding to the targetreceptor and can therefore drive the desired pharmacologic activity(Free drug theory (FDT) (Bohnert, T. et al. J. Pharmaceutical Sciences2013, 102, 2953-2994). As a consequence, high plasma protein binding mayalso have a negative impact on efficacy since it is the free fraction ofdrug that is responsible for the pharmacological action.

Plasma protein binding information can be used to estimate the unboundand thus effective concentration of drugs in order to establishpharmacokinetic/pharmacodynamic (PKPD) relationships in animals andhumans. The extent of plasma protein binding across species providesimportant information for PKPD modelling and helps to better understandtranslational aspects and/or efficacy differences between animal modelsand humans.

In the present invention, the introduction of a sulfoximine groupresults in an increased unbound fraction (decreased PPB) for compoundsof Formula (I). In addition, the preferred compounds of the inventionprovide a low variability of fractions unbound across several animalspecies including humans. As a consequence, free drug concentrations intissues are increased, directly yielding higher unbound brainconcentrations (as measured by cerebrospinal fluid concentrations assurrogate) with similar effects measurable across different specieswhich often greatly improve predictability of human PK and result inlower effective human dose due to the same extent of increase of unboundfractions across species (Liu et al. J. Med. Chem. 2014, 57, 8238).

It has been surprisingly found that the compounds according to theinvention and salts thereof have very valuable pharmacologicalproperties. Due to the substitution at the dihydrobenzofurane ringsystem by R′ and/or R″, the compounds achieve increased metabolicstability, as e.g. shown in microsome stability assays as compared totheir unsubstitued conterparts, without loosing their pharmaceuticalpotency.

Further, preferred glycosidase inhibitors of formula I provide increasedunbound, i.e. free fractions in plasma. Moreover, the preferredcompounds according to the invention and salts thereof consistentlyprovide increased free fractions in plasma across species includinghumans (low inter-species variability), which make them ideal forpharmaceutical development and their application as a drug.

The invention relates to compounds of formula (I)

-   -   wherein    -   R is straight chain or branched alkyl having 1 to 6 carbon        atoms, wherein 1 to 5 hydrogen atoms may be replaced by Hal or        OH;    -   W is CH or N;    -   X is N or CR′;    -   R′, R″ denote each independently H, Hal or straight chain or        branched alkyl having 1 to 12 carbon atoms, wherein at least one        of R and R″ is different from H;    -   R″ denotes H, Hal, NR³R⁴, CHR³R⁴, OR³, CN or a straight chain or        branched alkyl having 1 to 12 carbon atoms, wherein 1 to 3        CH₂-groups may be replaced by a group selected from O, NR³, S,        SO, SO₂, S(O)(NR^(3′)), N(SO)R^(3′), CO, COO, OCO, CONR³, NR³CO,

-   -    and wherein 1 to 5 hydrogen atoms may be replaced by Hal, NR³R⁴        or NO₂ or by one of the following groups:

-   -    or R″ denotes one of the following groups:

-   -   R³, R⁴ denote each independently H or a straight chain or        branched alkyl group having 1 to 12 carbon atoms;    -   Q denotes one of the following groups:

-   -   Y is N or CR;    -   Z¹ is S, O, NR³;    -   Z², Z³ independently denote CR⁵ or N;    -   Z⁴ is N, CH, CON, COCH;    -   Z⁵ is NR⁸, CHR⁵, S(O)(NR^(3′)), N(SO)R^(3′),

-   -   Z⁶ is CH₂, CO, SO₂, S(O)(NR^(3′)), N(SO)R^(3′),

-   -   Z⁷ is C(R^(3′))₂, S, O, NR^(3′);    -   s denotes 0 or 1;    -   T is N, CH or CR⁷;    -   R^(3′) denotes H or a straight chain or branched alkyl group        having 1 to 12 carbon atoms, wherein 1 to 3 CH₂-groups may be        replaced by a group selected from SO₂, CO, O and wherein 1 to 5        hydrogen atoms may be replaced by Hal;    -   R⁵, R⁶, R⁷ independently denote H, Hal, NR³R⁴, NO₂ or a straight        chain or branched alkyl having 1 to 12 carbon atoms, wherein 1        to 3 CH₂-groups may be replaced by a group selected from O, NR³,        S, SO, SO₂, S(O)(NR^(3′)), N(SO)R³′, CO, COO, OCO, CONR³, NR³CO

-   -    and wherein 1 to 5 hydrogen atoms may be replaced by Hal,        NR³R⁴, NO₂, OR³, Het, Ar, Cyc, or by one of the following        groups:

-   -    or R⁵, R⁶, R⁷ denote Ar, Het or Cyc or one of the following        groups:

-   -   R⁸ denotes H or straight chain or branched alkyl having 1 to 12        carbon atoms, wherein 1 to 3 CH₂-groups may be replaced by a        group selected from SO, SO₂, S(O)(NR^(3′)), N(SO)R^(3′), CO,        COO, OCO, CONR³, NR³CO, and

-   -   -   and further wherein 1 to 5 hydrogen atoms may be replaced by            CN, OR³, SR³, Hal, NR³R⁴, NO₂ or by one of the following            groups:

-   -   -    or R⁸ denote one of the following groups:

-   -   Hal denotes F, Cl, Br or I;    -   Het denotes a saturated, unsaturated or aromatic ring, being        monocyclic or bicyclic or fused-bicyclic and having 3- to        8-members and containing 1 to 4 heteroatoms selected from N, O        and S, which may be substituted by 1 to 3 substituents selected        from R⁵, Hal and OR³;    -   Ar denotes a 6-membered carbocyclic aromatic ring or a fused or        non-fused bicylic aromatic ring system, which is optionally        substituted by 1 to 3 substituents independently selected from        R⁵, OR³ and Hal;    -   Cyc denotes a saturated or an unsaturated carbocyclic ring        having from 3 to 8 carbon atoms which is optionally substituted        by 1 to 3 substituents independently selected from R⁵ or Hal or        OH;    -   m and n denote independently from one another 0, 1, 2 or 3, t        and q denote independently from one another 0, 1, 2 or 3, with        t+q>1;    -   and pharmaceutically usable derivatives, solvates, salts,        prodrugs, tautomers, enantiomers, racemates and stereoisomers        thereof, including mixtures thereof in all ratios and compounds        of formula I, wherein one or more H atoms are replaced by D        (deuterium).

Specifically, formula (I) includes the following two enantiomers offormula Ia and Ib:

wherein R, R′, R″, X, W, Q, n and m have the meaning given above.

The invention also relates to a mixture of, i.e. a compositioncomprising, compounds Ia and Ib as set out above, having identicalgroups R, R′, R″, X, W, Q, n and m in equal or unequal amounts.

Throughout the specification, R in formula I, Ia and Ib is preferablymethyl. The indices m and n in formula I, la, Ib and Ic are preferablysimultaneously 1.

Compounds of formula Ic are most preferred:

wherein R, R′, W, Q, n and m have the meaning given in above. In a verypreferred embodiment, R and R′ in formula Ic denote both methyl.

If individual groups and indices, such as R′ and m, occur more than oncein a compound of formula I, they can have the same or different meaningsaccording to the respective definition of that group.

Preferred compounds of the present invention are preferably used assingle isomer in their non-racemic form, i.e. as diasteromerically andenatiomerically pure compounds or their diastereomerically andenaniomerically enriched mixtures of the respective diastereomers andenantiomers. If R is an unsubstituted straight chain or branched alkylhaving 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl oriso-butyl, the S-configuration at this stereogenic center of compoundsof formula I is preferred. Very preferred are formulae Ib and B.

A further preferred compound of formula I is a single enantiopure orenantiomerically enriched diastereoisomer, i.e.a compound wherein thestereogenic center bearing the group R has an S-configuration and anyother stereogenic center within the compound has either an S- or anR-configuration.

In general, compounds of formula I are preferred that contain one oremore preferred groups such as R′ and indices such as m or n. Compoundsof formula I are the more preferred, the more preferred groups orindices they contain.

If substituents, such as the group R⁸, are connected to the remainder ofthe molecule through a heteroatom, the connecting atom in the respectivegroup is preferably a carbon atom, S-atom or the respective group is H.

The invention also relates to the use of compounds of formula (I) as amedicament.

In the meaning of the present invention, the compound is defined toinclude pharmaceutically usable derivatives, solvates, prodrugs,tautomers, enantiomers, racemates and stereoisomers thereof, includingmixtures thereof in all ratios.

The term “pharmaceutically usable derivatives” is taken to mean, forexample, the salts of the compounds according to the invention and alsoso-called prodrug compounds. The term “solvates” of the compounds istaken to mean adductions of inert solvent molecules onto the compounds,which are formed owing to their mutual attractive force. Solvates are,for example, mono- or dihydrates or alkoxides. The invention alsocomprises solvates of salts of the compounds according to the invention.The term “prodrug” is taken to mean compounds according to the inventionwhich have been modified by means of, for example, alkyl or acyl groups,sugars or oligopeptides and which are rapidly cleaved in the organism toform the effective compounds according to the invention. These alsoinclude biodegradable polymer derivatives of the compounds according tothe invention. It is likewise possible for the compounds of theinvention to be in the form of any desired prodrugs such as, forexample, esters, carbonates, carbamates, ureas, amides or phosphates, inwhich cases the actually biologically active form is released onlythrough metabolism. Any compound that can be converted in-vivo toprovide the bioactive agent (i.e. compounds of the invention) is aprodrug within the scope and spirit of the invention. Various forms ofprodrugs are well known in the art. It is further known that chemicalsubstances are converted in the body into metabolites which may whereappropriate likewise elicit the desired biological effect—in somecircumstances even in more pronounced form. Any biologically activecompound that was converted in-vivo by metabolism from any of thecompounds of the invention is a metabolite within the scope and spiritof the invention.

The compounds of the invention may be present in the form of theirdouble bond isomers as pure E or Z isomers, or in the form of mixturesof these double bond isomers. Where possible, the compounds of theinvention may be in the form of the tautomers, such as keto-enoltautomers. All stereoisomers of the compounds of the invention arecontemplated, either in a mixture or in pure or substantially pure form.The compounds of the invention can have asymmetric centers at any of thecarbon atoms. Consequently, they can exist in the form of theirracemates, in the form of the pure enantiomers and/or diastereomers orin the form of mixtures of these enantiomers and/or diastereomers. Themixtures may have any desired mixing ratio of the stereoisomers. Thus,for example, the compounds of the invention which have one or morecenters of chirality and which occur as racemates or as diastereomermixtures can be fractionated by methods known per se into their opticalpure isomers, i.e. enantiomers or diastereomers. The separation of thecompounds of the invention can take place by column separation on chiralor non-chiral phases or by re-crystallization from an optionallyoptically active solvent or with use of an optically active acid or baseor by derivatization with an optically active reagent such as, forexample, an optically active alcohol, and subsequent elimination of theradical.

The invention also relates to the use of mixtures of the compoundsaccording to the invention, for example mixtures of two diastereomers,for example in the ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000.These are particularly preferably mixtures of stereoisomeric compounds.

An enantiomerically enriched mixture denotes a compound of Formula (I)or related formula having an enantiomeric excess, as measured by methodswell known by one skilled in the art, of 10% or more, preferably 50% ormore, and more preferably more than 95%. Most preferably anenantiomerically enriched mixture denotes a compound of Formula (I) orrelated Formulae having an enantiomeric excess of more than 98%.

The nomenclature as used herein for defining compounds, especially thecompounds according to the invention, is in general based on the rulesof the IUPAC-organization for chemical compounds and especially organiccompounds. The compounds of invention have been named according to thestandards used in the program AutoNom 2000 or ACD Lab Version 12.01 orInstant JChem Version: 15.12.7.0. The determination of thestereochemistry (S) or (R) is performed using standard rules of thenomenclature well known by one skilled in the art. The terms indicatedfor explanation of the above compounds of the invention always, unlessindicated otherwise in the description or in the claims, have thefollowing meanings:

The term “unsubstituted” means that the corresponding radical, group ormoiety has no substituents. The term “substituted” means that thecorresponding radical, group or moiety has one or more substituents.Where a radical has a plurality of substituents, and a selection ofvarious substituents is specified, the substituents are selectedindependently of one another and do not need to be identical. Eventhough a radical has a plurality of a specific-designated substituentthe expression of such substituent may differ from each other (e.g.methyl and ethyl). It shall be understood accordingly that a multiplesubstitution by any radical of the invention may involve identical ordifferent radicals. Hence, if individual radicals occur several timeswithin a compound, the radicals can adopt any of the meanings indicated,independently of one another.

The term “alkyl” or “alkyl group” refers to acyclic saturated orunsaturated hydrocarbon radicals, which may be branched orstraight-chain and preferably have 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10carbon atoms, i.e. C₁-C₁₀-alkanyls. Examples of suitable alkyl radicalsare methyl, ethyl, n-propyl, isopropyl, 1,1-, 1,2- or2,2-dimethylpropyl, 1-ethylpropyl, 1-ethyl-1-methylpropyl,1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2-,1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, n-pentyl,iso-pentyl, neo-pentyl, tert-pentyl, 1-, 2-, 3- or -methyl-pentyl,n-hexyl, 2-hexyl, isohexyl, n-heptyl, n-octyl, n-nonyl, n-decyl,n-undecyl, n-dodecyl, n-tetradecyl, n-hexadecyl, n-octadecyl,n-icosanyl, n-docosanyl. In certain embodiments of the invention, 1 ormore, preferable 1 to 3 CH₂ groups may be replaced by other divalentgroups accoding to the defintions given above and below. In a particularembodiment, an H atom of alkyl may be replaced by Cyc.

In an embodiment of the invention, alkyl denotes unbranched or branchedalkyl having 1-10 C atoms, in which 1-7 H atoms may be replacedindependently from one another by Hal. A preferred embodiment of alkyldenotes unbranched or branched alkyl having 1-6 C atoms, in which 1-4atoms may be replaced independently from one another by Hal. In a morepreferred embodiment of the invention, alkyl denotes unbranched orbranched alkyl having 1-4 C atoms, in which 1-3 H atoms can be replacedindependently from one another by Hal, particularly by F and/or Cl. Itis most preferred that alkly denotes unbranched or branched alkyl having1-6 C atoms. Highly preferred is C₁₋₄-alkyl. A C₁₋₄-alkyl radical is forexample a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl,sec-butyl, tert-butyl, fluoromethyl, difluoromethyl, trifluoromethyl,pentafluoroethyl, 1,1,1-trifluoroethyl or bromomethyl, especiallymethyl, ethyl, propyl or trifluoromethyl. It shall be understood thatthe respective denotation of alkyl is independently of one another inany radical of the invention.

The terms “cycloalkyl” or “Cyc” for the purposes of this inventionrefers to saturated and partially unsaturated non-aromatic cyclichydrocarbon groups/radicals, having 1 to 3 rings, that contain 3 to 20,preferably 3 to 12, more preferably 3 to 9 carbon atoms. The cycloalkylradical may also be part of a bi- or polycyclic system, where, forexample, the cycloalkyl radical is fused to an aryl, heteroaryl orheterocyclyl radical as defined herein by any possible and desired ringmember(s). The bonding to the compounds of the general formula (I) canbe effected via any possible ring member of the cycloalkyl radical.Examples of suitable cycloalkyl radicals are cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl,cyclohexenyl, cyclopentenyl and cyclooctadienyl.

In an embodiment of the invention, Cyc denotes cycloalkyl having 3-7 Catoms, in which 1-4 H atoms may be replaced independently of one anotherby Hal. Preferred is C₃-C₇-cycloalkyl. More preferred isC₄-C₇-cycloalkyl. Most preferred is C₅-C₇-cycloalkyl, i.e. cyclopentyl,cyclohexyl or cycloheptyl, highly preferably cyclohexyl. It shall beunderstood that the respective denotation of Cyc is independently of oneanother in any radical of the invention.

The term “Ar”, “aryl” or “carboaryl” for the purposes of this inventionrefers to a mono- or polycyclic aromatic hydrocarbon systems having 3 to14, preferably 3-12, more preferably 4 to 12, most preferably 5 to 10,highly preferably 6 to 8 carbon atoms, which can be optionallysubstituted. The term “Ar” or “aryl” also includes systems in which thearomatic cycle is part of a bi- or polycyclic saturated, partiallyunsaturated and/or aromatic system, such as where the aromatic cycle isfused to an aryl, cycloalkyl, heteroaryl or heterocyclyl group asdefined herein via any desired and possible ring member of the arylradical. The bonding to the compounds of the general formula (I) can beeffected via any possible ring member of the aryl radical. Examples ofsuited aryl radicals are phenyl, biphenyl, naphthyl, 1-naphthyl,2-naphthyl and anthracenyl, but likewise indanyl, indenyl or1,2,3,4-tetrahydronaphthyl. Preferred carboaryls of the invention areoptionally substituted phenyl, naphthyl and biphenyl, more preferablyoptionally substituted monocylic carboaryl having 6-8 C atoms, mostpreferably optionally substituted phenyl.

Ar and aryl are preferably selected from the following group: phenyl,o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl,o-, m- or p-isopropylphenyl, o-, m- or p-tert.-butylphenyl, o-, m- orp-hydroxyphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl,o-, m- or p-fluoro-phenyl, o-, m- or p-bromophenyl, o-, m- orp-chlorophenyl, o-, m- or p-sulfonamidophenyl, o-, m- orp-(N-methyl-sulfonamido)phenyl, o-, m- orp-(N,N-dimethyl-sulfonamido)-phenyl, o-, m- orp-(N-ethyl-N-methyl-sulfonamido)phenyl, o-, m- orp-(N,N-diethyl-sulfonamido)-phenyl, particularly 2,3-, 2,4-, 2,5-, 2,6-,3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl,2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl,2,4,6-trimethoxyphenyl, 2-hydroxy-3,5-dichlorophenyl, p-iodophenyl,4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl,2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl,3-chloro-6-methoxyphenyl or 2,5-dimethyl-4-chlorophenyl.

Irrespective of further substitutions, Het denotes preferably 2- or3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, 4- or5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably1,2,3-triazoM-, -4- or -5-yl, 1,2,4-triazo-, -3- or 5-yl, 1- or5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl,1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl,1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-,3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-iso-5indolyl, indazolyl, 1-, 2-, 4-or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzo-pyrazolyl, 2-, 4-,5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-,5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-,5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7-or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo-1,4-oxazinyl, furtherpreferably 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl,2,1,3-benzothiadiazol-4-, -5-yl or 2,1,3-benzoxadiazol-5-yl,azabicyclo-[3.2.1]octyl or dibenzofuranyl.

The heterocyclic radicals may also be partially or fully hydrogenated.

Irrespective of further substitutions, Het can thus also denote,preferably, 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-,-4- or 5-furyl, tetra-hydro-2- or -3-furyl, 1,3-dioxolan-4-yl,tetrahydro-2- or -3-thienyl, 2,3-di-hydro-l-, -2-, -3-, -4- or-5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-,-2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl,1,4-dihydro-1-, -2-, -3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-,-4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl,1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl,hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl,1,2,3,4-tetrahydro-1-(-2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl,1,2,3,4-tetra-hydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-isoquinolyl,2-, 3-, 5-, 6-, 7- or 8-3,4-dihydro-2H-benzo-1,4-oxazinyl, furthermorepreferably 2,3-methylene-dioxyphenyl, 3,4-methylenedioxyphenyl,2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl,3,4-(difluoromethylenedioxy)phenyl, 2,3-dihydro-benzofuran-5- or 6-yl,2,3-(2-oxomethylenedioxy)phenyl or also3,4-di-hydro-2H-1,5-benzodioxepin-6- or -7-yl, furthermore preferably2,3-dihydrobenzofuranyl, 2,3-dihydro-2-oxofuranyl, 3,4-dihydro-2-oxo-1H-quinazolinyl, 2,3-dihydrobenzoxazolyl, 2-oxo-2,3-dihydrobenzoxazolyl,2,3-dihydrobenzimidazolyl, 1,3-dihydroindole, 2-oxo-1,3-dihydroindole or2-oxo-2, 3-dihydrobenzimidazolyl.

Het preferably denotes piperidinyl, 4-hydroxypiperidinyl, piperazinyl,4-methylpiperazinyl, pyrrolidinyl, morpholinyl, dihydro-pyrazolyl,dihydro-pyridyl, dihydropyranyl, furyl, thienyl, pyrrolyl, imidazolyl,pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl,pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl,pyridazinyl, pyrazinyl, quinolyl, isoquinolyl, benzimidazolyl,benzotriazolyl, indolyl, benzo-1,3-dioxolyl,2,3-dihydro-benzo[1,4]dioxinyl, indazolyl or benzothiadiazolyl, each ofwhich is unsubstituted or mono-, di- or trisubstituted.

The term “halogen”, “halogen atom”, “halogen substituent” or “Hal” forthe purposes of this invention refers to one or, where appropriate, aplurality of fluorine (F, fluoro), bromine (Br, bromo), chlorine (Cl,chloro) or iodine (I, iodo) atoms. The designations “dihalogen”,“trihalogen” and “perhalogen” refer respectively to two, three and foursubstituents, where each substituent can be selected independently fromthe group consisting of fluorine, chlorine, bromine and iodine. Halogenpreferably means a fluorine, chlorine or bromine atom. Fluorine andchlorine are more preferred, particularly when the halogens aresubstituted on an alkyl (haloalkyl) or alkoxy group (e.g. CF₃ and CF₃O).It shall be understood that the respective denotation of Hal isindependently of one another in any radical of the invention.

R is preferably straight chain alkyl having 1 to 4 carbon atoms, wherein1 to 5 hydrogen atoms may be replaced by Hal or OH. More preferably R ismethyl or ethyl, and most preferably methyl.

W is preferably N.

R^(3′) denotes preferably H, methyl, ethyl, 2-hydroxyethyl or2-methoxyethyl.

Preferably, the group S(O)(NR^(3′)) is selected from

Preferably, the group N(SO)R^(3′) is selected from

Q is preferably one of the following groups:

wherein T, Y, Z⁵, Z⁶, R′″, R⁵, R⁶, R⁷ and R⁸ have the meaning givenabove.

Q is especially preferred one of the following groups:

wherein R^(3′) has the meaning given above and is preferably H, methyl,ethyl, 2-hydroxyethyl or 2-methoxyethyl.

R⁵, R⁶ and R⁷ are preferably independently H, SO₂CH₃, SO₂CH₂CH₃,SO₂CH₂CH₂OH, SO₂CH₂CH₂OCH₃, S(O)(NR^(3′))CH₃, S(O)(NR^(3′))CH₂CH₃,S(O)(NR^(3′))CH₂CH₂OH, S(O)(NR^(3′))CH₂CH₂OCH₃, N(SO)R^(3′)CH₃,N(SO)R^(3′)CH₂CH₃, N(SO)R^(3′)CH₂CH₂OH, N(SO)R^(3′)CH₂CH₂OCH₃,

Hal, NR³R⁴, NO₂, phenyl, 2-, 3- or 4-hydroxy or methoxyphenyl, alkyl,preferably methyl, ethyl, isopropyl, isobutyl, tert-butyl, CF₃, alkoxy(Oalkyl), preferably methoxy or ethoxy, hydroxyalkylen, preferablyCH₂OH, CH₂CH₂OH, alkoxyalkylen preferably CH₂CH₂OCH₃, COOH, COOalkyl,preferably COOCH₃, COOCH₂CH₃, CONHalkyl, preferably CONHCH₃, CONHCH₂CH₃,CONHisopropyl, CONHcyclohexyl, CONH₂, CON(CH₃)₂, NHCOalkyl, preferablyNHCOCH₃, NHCOCH₂CH₃, NHCOPropyl, NHCOisopropyl, NHCOcyclopropyl,NHCO-4-Chloro-phenyl, NHCH₂CH₃, NHCH₂CH₂CH₃, NHCOCH₂CH₂OH,CO—N-morpholinyl, CON(CH₃)CH₂CH₂N(CH₃)₂, CO-1-piperidinyl,CO-4-hydroxy-1-piperidinyl, CO-1-piperazinyl, CO-4-methyl-1-piperazinyl,CH₂—N— morpholinyl, CH₂N(H)COCH₃, CH₂N(CH₃)COCH₃, CH₂NH₂, NH₂,CH(OH)CH₃, CH(OR³)CH₃ or a group selected from

wherein t+q is 2 or 3.

R⁸ is preferably a group selected from H, COalkyl or alkyl or hydroxylalkyl. More preferably, R⁸ is H, COmethyl or methyl.

T is preferably N or CH, most preferably N.

Z¹ is preferably S or NH.

Z², Z³ preferably denote independently CH or N.

Z⁴ is preferably N or CH.

Z⁵ is preferably is NR⁸, CHR⁵.

Z⁶ is preferably CH₂, CO or SO₂.

Z⁷ is preferably CH₂, S, O, NH. If Z⁷ is S, O, NR^(3′), t and q are each1 or one of t and q is 1 while the other denotes 2.

Most preferably, t and q simultaneously denote 1.

In a particularly preferred embodiment, compounds of formula Id aredefined as given below:

-   -   Wherein Q has the meaning given above,    -   and pharmaceutically usable derivatives, solvates, salts,        prodrugs, tautomers, enantiomers, racemates and stereoisomers        thereof, including mixtures thereof in all ratios and compounds        of formula I, wherein one or more H atoms are replaced by D        (deuterium).

Throughout the specification and claims, the individual groups such asCOO, CONR³ can be attached through any of the linking atoms to the restof the compound of formula I, i.e. a respective part of the compound offormula I may be attached to the right or left or lower or upper side ofthe individual group as presented in the specification.

Accordingly, the subject-matter of the invention relates to compounds offormula (I) as medicament, in which at least one of the aforementionedradicals has any meaning, particularly realize any preferred embodiment,as described above. Radicals, which are not explicitly specified in thecontext of any embodiment of formula (I), sub-formulae thereof or otherradicals thereto, shall be construed to represent any respectivedenotations according to formula (I) as disclosed hereunder for solvingthe problem of the invention. That means that the aforementionedradicals may adopt all designated meanings as each described in theprior or following course of the present specification, irrespective ofthe context to be found, including, but not limited to, any preferredembodiments. It shall be particularly understood that any embodiment ofa certain radical can be combined with any embodiment of one or moreother radicals.

Particularly highly preferred embodiments are those compounds of formula(I) listed in Table 1 and/or physiologically acceptable salts thereof.

TABLE 1 Compounds of formulae (I). OGA enzyme inhibition assay:Configuration OGA IC50 No Structure specification (M) 1

Racemic ++++ 2

Racemic ++++ 3

Racemic ++++ 4

Racemic + 5

Racemic + 6

Racemic + 7

Racemic +++ 8

Racemic ++ 9

Synthesized from (R)-propane-1,2- diol ++++ 10

Synthesized from (R)-propane-1,2- diol ++++ 11

Chiral SFC Method A: 1st eluting compound ++ 12

Chiral SFC Method A: 2nd eluting compound ++++ 13

Chiral SFC Method A: 1st eluting compound ++++ 14

Synthesized from (S)-propane-1,2- diol ++ 15

Synthesized from (S)-propane-1,2- diol ++ 16

Chiral SFC Method B: 1st eluting compound ++ 17

Chiral SFC Method B: 2nd eluting compound +++ 18

Chiral SFC Method C: 1st eluting compound +++ 19

Synthesized from (R)-propane-1,2- diol ++++ 20

Synthesized from (R)-propane-1,2- diol ++++ 21

Synthesized from (R)-propane-1,2- diol +++

Activity range of the compounds of Formula (I) is the following:

+ 1 to 10 μM ++ 0.2 to 1 μM +++ 0.2 to 0.05 μM ++++ below 0.05 μM

Preferred compounds of the present invention demonstrate adequateproperties for use as a drug. In particular, such preferred compoundsshow a high solid state stability, high stability in the presence ofliver microsome, high oxidation stability and suitable permeability.Further preferred compounds of the present invention demonstrate theirsuitability as drugs by potent biological activity, such as the level ofO-GlcNAcylation of total proteins measured in brain extracts. Relevanttests for determining such parameters are known by the person skilled inthe art, e.g. solid state stability (Waterman K. C. (2007) Pharm Res24(4); 780-790), stability in the presence of liver microsome (Obach R.S. (1999) Drug Metab Dispos 27(11); 1350-135) and the permeability (e.g.Caco-2 permeability assay, Calcagno A. M. (2006) Mol Pharm 3(1); 87-93);alternatively, they are described in Examples below, such as Example B02describing the determination of O-GlcNAcylation level of total proteinsmeasured in brain extracts. Compounds of the present invention that showa high potency in OGA inhibition assays and one or more of the aboveproperties are especially suitable as a drug for the indicationsmentioned in the present specification.

The compounds according to formula (I) and the starting materials forits preparation, respectively, are produced by methods known per se, asdescribed in the literature, i.e. under reaction conditions that areknown and suitable for said reactions.

Use can also be made of variants that are known per se, but are notmentioned in greater detail herein. If desired, the starting materialscan also be formed in-situ by leaving them in the un-isolated status inthe crude reaction mixture, but immediately converting them further intothe compound according to the invention. On the other hand, it ispossible to carry out the reaction stepwise.

The following abbreviations refer respectively to the definitions below:

Ac (acetyl), aq (aqueous), h (hour), g (gram), L (liter), mg(milligram), MHz (Megahertz), μM (micromolar), min (minute), mm(millimeter), mmol (millimole), mM (millimolar), m.p. (melting point),equiv (equivalent), mL (milliliter), μL (microliter), ACN(acetonitrile), AcOH (acetic acid), BINAP(2,2′-bis(disphenylphosphino)-1,1′-binaphthalene, BOC(tert-butoxy-carbonyl), CBZ (carbobenzoxy), CDCl₃ (deuteratedchloroform), CD₃OD (deuterated methanol), CH₃CN (acetonitrile), c-hex(cyclohexane), DCC (dicyclohexyl carbodiimide), DCM (dichloromethane),DHP (O-(2,4-dinitrophenyl)-hydroxylamine), dppf(1,1′-bis(diphenylphosphino)ferrocene), DIC (diisopropyl carbodiimide),DIEA (diisopropylethyl-amine), DMF (dimethylformamide), DMSO(dimethylsulfoxide), DMSO-d₆ (deuterated dimethylsulfoxide), EDC(1-(3-dimethyl-amino-propyl)-3-ethylcarbodiimide), ESI (Electro-sprayionization), EtOAc (Ethyl acetate), Et₂O (diethyl ether), EtOH(ethanol), FMOC (fluorenylmethyloxycarbonyl), HATU(dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammoniumhexafluorophosphate), HPLC (High Performance Liquid Chromatography),i-PrOH (2-propanol), K₂CO₃ (potassium carbonate), LC (LiquidChromatography), m-CPBA (3-chloroperbenzoic acid), MD Autoprep (Massdirected Autoprep), MeOH (methanol), MgSO₄ (magnesium sulfate), MS (massspectrometry), MTBE (Methyl tert-butyl ether), Mtr. (4-Methoxy-2, 3,6-trimethylbenzensulfonyl), MW (microwave), NBS (N-bromo succinimide),NaHCO₃ (sodium bicarbonate), NaBH₄ (sodium borohydride), NMM (N-methylmorpholine), NMR (Nuclear Magnetic Resonance), MSH(O-mesitylenesulfonylhydroxylamine), POA (phenoxyacetate), Py(pyridine), PyBOP® (benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphoniumhexafluorophosphate), RT (room temperature), Rt (retention time), SFC(supercritical fluid chromatography), SPE (solid phase extraction), T3P(propylphosphonic anhydride), TBAF (tetra-n-butylammonium fluoride),TBTU (2-(1-H-benzotriazole-1-yl)-1,1,3,3-tetramethyluromium tetrafluoroborate), TEA (triethylamine), TFA (trifluoroacetic acid), THF(tetrahydrofurane), TLC (Thin Layer Chromatography), UV (Ultraviolet).

In general, the compounds according to Formula (I) and related formulaeof this invention may be prepared from readily available startingmaterials. If such starting materials are not commercially available,they may be prepared by standard synthetic techniques. In general, thesynthesis pathways for any individual compound of Formula (I) andrelated formulae will depend on the specific substituents of eachmolecule, such factors being appreciated by those having ordinary skillin the art. The following general methods and procedures describedhereinafter in the examples may be employed to prepare compounds ofFormula (I) and related formulae. Reaction conditions depicted in thefollowing schemes, such as temperatures, solvents, or co-reagents, aregiven as examples only and are not restrictive. It will be appreciatedthat where typical or preferred experimental conditions (i.e. reactiontemperatures, time, moles of reagents, solvents etc.) are given, otherexperimental conditions can also be used unless otherwise stated.Optimum reaction conditions may vary with the particular reactants orsolvents used, but such conditions can be determined by a person skilledin the art, using routine optimisation procedures. For all theprotection and deprotection methods, see Philip J. Kocienski, in“Protecting Groups”, Georg Thieme Verlag Stuttgart, New York, 1994 and,Theodora W. Greene and Peter G. M. Wuts in “Protective Groups in OrganicSynthesis”, Wiley Interscience, 3^(rd) Edition 1999.

A “leaving group” LG denotes a chemical moiety which can be removed orreplaced by another chemical group. Throughout the specification, theterm leaving group preferably denotes Cl, Br, I or a reactively modifiedOH group, such as, for example, an activated ester, an imidazolide oralkylsulfonyloxy having 1 to 6 carbon atoms (preferablymethylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxyhaving 6 to 10 carbon atoms (preferably phenyl- or p-tolylsulfonyloxy).When a leaving group LG is attached to an aromatic or heteroaromaticring, LG can denote in addition SO₂-alkyl or F. Radicals of this typefor activation of the carboxyl group in typical acylation reactions aredescribed in the literature (for example in the standard works, such asHouben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart). Activated esters areadvantageously formed in situ, for example through addition of HOBt,N-hydroxysuccinimide or HATU.

Depending on the nature of R′, R″, X, R, W, Q, m and n, differentsynthetic strategies may be selected for the synthesis of compounds ofFormula (I). In the process illustrated in the following schemes, R′,R″, X, R, W, Q, m and n are as above-defined in the description unlessotherwise mentioned.

Compounds of Formula (I), wherein R′, R″, X, R, W, Q, m and n aredefined as above, can be prepared from alternative compounds of Formula(I), using suitable interconversion procedures such as those describedhereinafter in the examples, or conventional interconversion procedureswell known by one skilled in the art.

Compound of formula (I) can be separated into compounds of formula (Ia)and (Ib) by chiral chromatography or by chiral resolution,re-crystallization with use of an optically active acid, using methodsknown by one skilled in the art and as described below in the examples(Scheme 1).

Compounds of formula (Ic), wherein R′, R″, X, R, Q, m and n are definedas above and W═N, can be prepared by the addition of an amine of formula(II) to a heterocycle of formula (III), where LG is a leaving group asdefined above. This addition can be performed under thermic conditions,heating both compounds at a temperature between 50° C. and 200° C.,using regular heating or microwave irradiation, in the presence of abase, such as but not limited to TEA, DIEA, K₂CO₃ or Cs₂CO₃, in a polarsolvent, e.g. DMF, DMA or NMP. Alternatively, this addition can becatalysed by a metal complex, such as but not limited to PdCl₂,Pd(OAc)₂, Pd₂(dba)₃ in the presence of a ligand, e.g. BINAP, o-Tol₃P,X-Phos, and a base, e.g. NaOtBu, Cs₂CO₃ or K₂CO₃, in a suitable solventor solvent mixture, for example dioxane, Toluene/MeOH, at a temperaturebetween RT to 150° C., preferably at RT, for a few hours, e.g. one hourto 24 h (Scheme 2). Amine of formula (II) is obtained after deprotectionof compound (IVa). PG is a suitable protecting group, which iscompatible with the chemistry described below, such as but not limitedto BOC. It can be removed under acidic conditions, such as but notlimited to HCl in MeOH or dioxane or TFA in DCM, yielding isolation ofamine (II).

Compounds of formula (Id), wherein R′, R″, X, R, Q, m and n are definedas above and W═CH, can be prepared from an ester (IVb) using methodknown by a person killed in the art and as described in the examplesbelow. Different heterocycles Q can be prepared from esterfunctionality, such as but not limited to oxadiazole, thiadiazole andthiazole, (Jakopin, Z. et al. Curr. Org. Chem. 2008, 12, 850-898.Hemming, K. Science of Synthesis, 2004, 13, 127-184. Augustine, J. K. etal. Tetrahedron, 2009, 65, 9989-9996. 37. Kempson, J. Name Reactions inHeterocyclic Chemistry II (2011), 299-308). Depending on the nature ofQ, compound of formula (Id) can be obtained from compound (IVc) bydisplacement of the leaving group LG, as defined above, in the presenceof a base such as but not limited to Cs₂CO₃ in a polar solvent, e.g.DMF, DMSO or NMP (Scheme 3). Alternatively compound of formula (Id) canbe prepared by metal catalysed cross coupling reaction with a suitableboronic acid (Va) or ester (Vb) and an heterocycle of formula (III),using conditions known by a person skilled in the art, such as but notlimited to Pd(PPh₃)₄ as catalyst, K₂CO₃ as base, dioxane as solvent attemperature ranging from RT to 180° C. (Scheme 3). Hydrogenation of theresulting coupling product in the presence of a catalyst such asPd(OH)₂, would yield compound of formula (Id) (e.g. Andres, J.-I. et al.J. Med. Chem. 2012, 55, 8685-8699) (Scheme 3).

Compound of formula (IV), wherein R′, R″, X, R, W, m and n are definedas above and Y¹ is a protecting group PG when W═N or an ester when W═CH,can be prepared from the corresponding ketone (IX) by reductiveamination with amine (VI), using conditions known to the one skilled inthe art, such as but not limited to the use of NaBH(OAc)₃ as reducingagent, in the presence of one equivalent of AcOH in DCE. Alternatively,reductive amination can be performed in two steps, with first imineformation, that can be catalysed by Ti(OiPr)₄, followed by reductionwith suitable reducing agent, such as but not limited to NaBH₄ in MeOH(Abdel-Magid, A. F. at al. J. Org. Chem. 1996, 61, 3849-3862).Alternatively, ketone (IX) can be reduced into the corresponding alcohol(VIII) using usual reductive agents such as NaBH₄ in an alcoholicsolvent, such as MeOH. Alcohol functionality can be then transformedinto a suitable leaving group, such as but not limited to Cl or OMs,using conditions known to a person skilled in the art. The addition ofamine (VI) to intermediate (VII) would yield the formation of compound(IV).

Alternatively, compound of formula (X), wherein W, Q, m and n aredefined as above and PG is a suitable protecting group, such as but notlimited to BOC, can be prepared from amine (XI), from compounds (XII),wherein m, n and PG are defined as above and Y² is an ester or a leavinggroup, or from compounds (XIIIa) or (XIIIb) (Scheme 5).

When W is N, compound of formula (X) can be prepared by the addition ofan amine of formula (XI) to a heterocycle of formula (III), where LG isa leaving group as defined above. This addition can be performed underthermic conditions or can be catalysed by a metal complex, usingconditions known by a person skilled in the art and as described belowin the examples.

When W is CH, compound of formula (X) can be prepared from an ester(XII), wherein Y²═COOR and W═CH, using method known by a person skilledin the art and as described in the examples below. Differentheterocycles Q can be prepared from ester functionality, such as but notlimited to oxadiazole, thiadiazole and thiazole, (Jakopin, Z. et al.Curr. Org. Chem. 2008, 12, 850-898. Hemming, K. Science of Synthesis,2004, 13, 127-184. Augustine, J. K. et al. Tetrahedron, 2009, 65,9989-9996. 37. Kempson, J. Name Reactions in Heterocyclic Chemistry II(2011), 299-308). Depending on the nature of Q, compound of formula (X)can be obtained from compound (XII), wherein W is CH and Y²=LG asdefined above, by displacement of the leaving group LG in the presenceof a base such as but not limited to Cs₂CO₃ in a polar solvent, e.g.DMF, DMSO or NMP. Compound of formula (X), wherein Q is a thiazole, canbe obtained from compound (XII), wherein Y² is anaminomethanecarbothioyl group, and a suitable alpha-bromo ketone, usingconditions know by a person skilled in the art.

Alternatively, compound of formula (X) can be prepared by metalcatalysed cross coupling reaction with a suitable boronic acid (XIIIa)or ester (XIIIb), and a heterocycle of formula (III), using conditionsknown by a person skilled in the art, such as but not limited toPd(PPh₃)₄ as catalyst, K₂CO₃ as base, dioxane as solvent at temperatureranging from RT to 180° C. (Scheme 5). Hydrogenation of the resultingcoupling product in the presence of a catalyst such as Pd(OH)₂, wouldyield compound of formula (X) (e.g. Andres, J.-I. et al. J. Med. Chem.2012, 55, 8685-8699) (Scheme 5).

PG is a suitable protecting group, which is compatible with thechemistry described above, such as but not limited to BOC. It can beremoved under acidic conditions, such as but not limited to HCl in MeOHor dioxane or TFA in DCM, yielding isolation of amine (XIV). It can befurther transformed into compound of formula (I) by reductive alkylationwith ketone of formula (IX), following conditions well known by a personskilled in the art, as described in the examples (Abdel-Magid, A. F. atal. J. Org. Chem. 1996, 61, 3849-3862). Alternatively, amine (XIV)addition to compound (VII), prepared as described above and in theexamples, would yield the formation of compound of formula (I).

Amine of formula (II) can be separated into amines of formula (IIa) and(IIb) by chiral chromatography or chiral resolution byre-crystallization with an optically active acid, using methods known byone skilled in the art and as described below in the examples (Scheme6).

Alternatively, amines of formula (IIa) and (lib) can be synthesized fromchiral amines (XVIa) and (XVIb) respectively, wherein R′, R″, X, R aredefined as above. Addition of amines (XVIa) and (XVIb) to reagent (XV),wherein PG is a protecting group, e.g. BOC or SO₂Tol and LG is a leavinggroup, e.g. Cl, would yield the formation of protected amines (IVe) and(lVf) respectively (Thiel, O. R. et al. J. Org. Chem. 2008, 73,3508-3515). Deprotection conditions need to be selected based on thenature of the PG, such as HCl in dioxane or MeOH or TFA in DCM for BOCprotecting group. Alternatively a mixture of HBr, AcOH and4-hydroxybenzoic acid or a mixture of H₂SO₄ and trifluoroacetic acid attemperatures ranging from RT to 100° C. would be used to cleave asulfonamide protecting group, such as para-toluene sulfonamide.

For the preparation of amines of formula (XVIa) and (XVIb), ketone offormula (IX) can be transformed into chiral imine (XVIII), reacting witha chiral auxiliary, such as but not limited to tert-butanesulfinamidegroup in the presence of titanium ethoxide (Ellman J. A. et al. Acc.Chem. Res. 2002, 35, 984-995). It can be further transformed intosulfinamide (XVIIa) or (XVIIb), depending on the conditions used for thereduction step, as described in the reference from Ellman J. A. et al.J. Org. Chem. 2007, 72, 626-629.

Alternatively aldehyde of formula (XIX) can be transformed into alcoholof formula (VIII) with addition of a suitable nucleophile, such as butnot limited to a Grignard reagent (Scheme 9). In another process, ketoneof formula (IXa) can be obtained by Stille cross coupling reactionbetween aryl halide (XX) and tributyl(1-ethoxyvinyl)tin in the presenceof a catalyst, such as but not limited to Pd(PPh₃)₂Cl₂ in toluene attemperatures ranging from RT to 110° C. (Scheme 10).

Ketone of formula (IXb), wherein R″ is defined as above and R′ ismethyl, can be obtained from 3-acetylphenol (XXIa). Its alkylation withR″-substituted allyl bromide in the presence of a base, such as but notlimited to K₂CO₃ or Cs₂CO₃, followed by a Claisen rearrangement, yieldsa mixture of regioisomers (XXIc) and (XXId). Metal catalyzed cyclizationof (XXId) regioisomer, using for example ZrCl₄ as metal catalyst, yieldsketone of formula (IXb) (Scheme 11).

Alternatively, aldehydes of formula (XIXa) or (XIXb) can be obtainedstarting from 1,4-dibromo-2-fluorobenzene (Scheme 12). Aromaticsubstitution with alcohols of formula (XXIIa) followed by esterreduction, yielded alcohol (XXVa). Alternatively, compound (XXIIb) canbe obtained by additionof alcohols of formula (XXIIb) to1,4-dibromo-2-fluorobenzene, followed by a deprotection step. Alcoholfunctionalities of (XXVa) or (XXVb) can be then transformed into asuitable leaving group LG, such as but not limited to Br, Cl or OMs,using conditions known to a person skilled in the art. Halogen metalexchange using for example n-butyl lithium, trigger dihydrobenzofurancyclization and followed by the addition of a formyl group with thesubsequent addition of DMF.

The sulfoximine group and related functionalities as indicated in thedefinitions can be introduced or generated at any stage of the synthesisof compounds of formula (I), as described below in the examples usingmethods known by one skilled in the art (Frings, M. et al. Eur. J. Med.Chem. 2017, 126, 225-245 and cited references).

When a reaction is preferably performed under basic conditions, asuitable base might be selected from metal oxides, e.g. aluminum oxide,alkaline metal hydroxide (potassium hydroxide, sodium hydroxide andlithium hydroxide, inter alia), alkaline earth metal hydroxide (bariumhydroxide and calcium hydroxide, inter alia), alkaline metal alcoholates(potassium ethanolate and sodium propanolate, inter alia), alkalinemetal carbonates (e.g., sodium bicarbonate) and several organic bases(e.g., N,N-diisopropylethylamine, piperidine or diethanolamine, interalia).

The reaction is generally carried out in an inert solvent. Suitableinert solvents are, for example, hydrocarbons, such as hexane, petroleumether, benzene, toluene or xylene; chlorinated hydrocarbons, such astrichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroformor dichloromethane; alcohols, such as methanol, ethanol, isopropanol,n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether,diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, suchas ethylene glycol monomethyl or monoethyl ether, ethylene glycoldimethyl ether (diglyme); ketones, such as acetone or butanone; amides,such as acetamide, dimethylacetamide or dimethylformamide (DMF);nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide(DMSO); carbon disulfide; carboxylic acids, such as formic acid, aceticacid or trifluoroacetic acid (TFA); nitro compounds, such asnitromethane or nitrobenzene; esters, such as ethyl acetate, or mixturesof the said solvents. Particular preference is given to TFA, DMF,dichloromethane, THF, H₂O, methanol, tert. butanol, tert. amylalcohol,triethylamine or dioxane.

Depending on the conditions used, the reaction time is between a fewminutes and 14 days, the reaction temperature is between about −80° C.and 140° C., normally between −50° C. and 120° C., preferably between−20° C. and 100° C.

The compounds of formula (I) and sub-formulae thereof are accessible viathe routes above. The starting materials, are usually known to theskilled artisan, or they can be easily prepared by known methods.

The compounds of formula (I) can be modified, like hydrogenated ormetal-reduced, to remove the chlorine, or put into a substitutionreaction, and/or to be transformed with an acid or base into a salt,preferably with a strong acid. Numerous papers and methods are availableand useful for the one skilled in the art in respect for organicchemistry, chemical strategies and tactics, synthetic routes, protectionof intermediates, cleavage and purification procedure, isolation andcharacterization. General chemical modifications are known to the oneskilled in the art. Halogenation of aryls or hydroxy substitution byhalogens of acids, alcohols, phenols, and their tautomeric structurescan be preferably carried out by use of POCl₃, or SOCl₂, PCl₅, SO₂Cl₂.In some instances oxalyl chloride is also useful. Temperatures can varyfrom 0° C. to reflux depending on the task to halogenate a pyridonestructure or a carboxylic acid or a sulfonic acid. Time will also beadjusted from minutes to several hours or even over night. Similarly,alkylation, ether formation, ester formation, amide formation are knownto the one skilled in the art. Arylation with aryl boronic acids can beperformed in presence of a Pd catalyst, appropriate ligand and base,preferably a carbonate, phosphate, borate salt of sodium, potassium orcesium. Organic bases, like Et₃N, DIPEA or the more basic DBU can alsobe used. Solvents can vary too, from toluene, dioxane, THF, diglyme,monoglyme, alcohols, DMF, DMA, NMP, acetonitrile, in some cases evenwater, and others. Commonly used catalysts like Pd (PPh₃)₄, or Pd(OAc)₂,PdCl₂ type precursors of PdO catalysts have advanced to more complexones with more efficient ligands. In C—C arylations, instead of boronicacids and esters, aryl-trifluoroborate potassium salts (Suzuki-Miyauracoupling), organo silanes (Hiyama coupling), Grignard reagents (Kumada),organozinc compounds (Negishi coupling) and stannanes (Stille coupling)may be useful. This experience can be transferred to N- andO-arylations. Numerous papers and methods are available and useful forthe one skilled in the art in respect of N-arylation and even ofelectron deficient anilines, and with aryl chlorides and anilines aswell as for O-arylation by using Cu catalysis and Pd catalysis.

In the final step of the processes above, a salt of the compounds,preferably those of formula (I), is optionally provided. The saidcompounds according to the invention can be used in their final non-saltform. On the other hand, the present invention also encompasses the useof these compounds in the form of their pharmaceutically acceptablesalts, which can be derived from various organic and inorganic acids andbases by procedures known in the art. Pharmaceutically acceptable saltforms of the compounds according to the invention are for the most partprepared by conventional methods. If the compound according to theinvention contains a carboxyl group, one of its suitable salts can beformed by the reaction of the compound with a suitable base to give thecorresponding base-addition salt. Such bases are, for example, alkalimetal hydroxides, including potassium hydroxide, sodium hydroxide andlithium hydroxide; alkaline earth metal hydroxides, such as magnesiumhydroxide, calcium hydroxide and barium hydroxide; alkali metalalkoxides, for example potassium ethoxide and sodium propoxide; andvarious organic bases, such as piperidine, diethanolamine andN-methyl-glucamine (meglumine), benzathine, choline, diethanolamine,ethylenediamine, benethamine, diethylamine, piperazine, lysine,L-arginine, ammonia, triethanolamine, betaine, ethanolamine, morpholineand tromethamine. The aluminum salts of the compounds according to theinvention are likewise included. In the case of certain compounds of theformula I, which contain a basic center, acid-addition salts can beformed by treating these compounds with pharmaceutically acceptableorganic and inorganic acids, for example hydrogen halides, such ashydrogen chloride, hydrogen bromide or hydrogen iodide, other mineralacids and corresponding salts thereof, such as sulfate, nitrate orphosphate and the like, and alkyl- and monoarylsulfonates, such asmethanesulfonate, ethanesulfonate, toluenesulfonate andbenzenesulfonate, and other organic acids and corresponding saltsthereof, such as carbonate, acetate, trifluoroacetate, tartrate,maleate, succinate, citrate, benzoate, salicylate, ascorbate and thelike. Accordingly, pharmaceutically acceptable acid-addition salts ofthe compounds according to the invention include the following: acetate,adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate(besylate), bisulfate, bisulfite, bromide, butyrate, camphorate,camphorsulfonate, caprate, caprylate, chloride, chlorobenzoate, citrate,cyclamate, cinnamate, cyclopentanepropionate, digluconate,dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate,formate, glycolate, fumarate, galacterate (from mucic acid),galacturonate, glucoheptanoate, gluconate, glutamate, glycerophosphate,hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate,hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate,iodide, isethionate, isobutyrate, lactate, lactobionate, malate,maleate, malonate, mandelate, metaphosphate, methanesulfonate,methylbenzoate, monohydrogenphosphate, 2-naphthalenesulfonate,nicotinate, nitrate, oxalate, oleate, palmoate, pectinate, persulfate,phenylacetate, 3-phenylpropionate, phosphate, phosphonate, phthalate,but this does not represent a restriction.

Both types of salts may be formed or interconverted preferably usingion-exchange resin techniques.

With regard to that stated above, it can be seen that the expressions“pharmaceutically acceptable salt” and “physiologically acceptablesalt”, which are used interchangeable herein, in the present connectionare taken to mean an active ingredient which comprises a compoundaccording to the invention in the form of one of its salts, inparticular if this salt form imparts improved pharmacokinetic propertieson the active ingredient compared with the free form of the activeingredient or any other salt form of the active ingredient used earlier.The pharmaceutically acceptable salt form of the active ingredient canalso provide this active ingredient for the first time with a desiredpharmacokinetic property which it did not have earlier and can even havea positive influence on the pharmacodynamics of this active ingredientwith respect to its therapeutic efficacy in the body.

The above-mentioned pharmaceutical salts which are preferred includeacetate, trifluoroacetate, besylate, citrate, fumarate, gluconate,hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate,mandelate, me-glumine, nitrate, oleate, phosphonate, pivalate, sodiumphosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate,tosylate and tro-meth-amine, but this is not intended to represent arestriction.

The acid-addition salts of basic compounds of the formula (I) areprepared by bringing the free base form into contact with a sufficientamount of the desired acid, causing the formation of the salt in aconventional manner. The free base can be regenerated by bringing thesalt form into contact with a base and isolating the free base in aconventional manner. The free base forms differ in a certain respectfrom the corresponding salt forms thereof with respect to certainphysical properties, such as solubility in polar solvents; for thepurposes of the invention, however, the salts otherwise correspond tothe respective free base forms thereof.

As mentioned, the pharmaceutically acceptable base-addition salts of thecompounds of the formula I are formed with metals or amines, such asalkali metals and alkaline earth metals or organic amines. Preferredmetals are sodium, potassium, magnesium and calcium. Preferred organicamines are N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanol-amine, ethylenediamine, N-methyl-D-glucamine and procaine.This is not intended to represent a restriction.

The base-addition salts of acidic compounds of the formula I areprepared by bringing the free acid form into contact with a sufficientamount of the desired base, causing the formation of the salt in aconventional manner. The free acid can be regenerated by bringing thesalt form into contact with an acid and isolating the free acid in aconventional manner. The free acid forms differ in a certain respectfrom the corresponding salt forms thereof with respect to certainphysical properties, such as solubility in polar solvents; for thepurposes of the invention, however, the salts otherwise correspond tothe respective free acid forms thereof.

If a compound of the formula (I) contains more than one group which iscapable of forming pharmaceutically acceptable salts of this type, theformula I also encompasses multiple salts. Typical multiple salt formsinclude, for example, bitartrate, diacetate, difumarate, dimeglumine,di-phosphate, disodium and trihydrochloride, but this is not intended torepresent a restriction.

With regard to that stated above, it can be seen that the expressions“pharmaceutically acceptable salt” and “physiologically acceptablesalt”, which are used interchangeable herein, in the present connectionare taken to mean an active ingredient which comprises a compoundaccording to the invention in the form of one of its salts, inparticular if this salt form imparts improved pharmacokinetic propertieson the active ingredient compared with the free form of the activeingredient or any other salt form of the active ingredient used earlier.The pharmaceutically acceptable salt form of the active ingredient canalso provide this active ingredient for the first time with a desiredpharmacokinetic property which it did not have earlier and can even havea positive influence on the pharmacodynamics of this active ingredientwith respect to its therapeutic efficacy in the body.

Owing to their molecular structure, the compounds of the formula (I) canbe chiral and can accordingly occur in various enantiomeric forms. Theycan therefore exist in racemic or in optically active form.

Since the pharmaceutical activity of the racemates or stereoisomers ofthe compounds according to the invention may differ, it may be desirableto use the enantiomers. In these cases, the end product or even theIntermediates can be separated into enantiomeric compounds by chemicalor physical measures known to the person skilled in the art or evenemployed as such in the synthesis.

In the case of racemic amines, diastereomers are formed from the mixtureby reaction with an optically active resolving agent. Examples ofsuitable resolving agents are optically active acids, such as the (R)and (S) forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaricacid, di-O-p-toluoyl-tartaric acid, mandelic acid, malic acid, lacticacid, suitable N-protected amino acids (for example N-benzoylproline orN-benzenesulfonylproline), or the various optically activecamphorsulfonic acids. The suitably formed salt with optically activeacid is crystallized using various combinations of solvents, such as butnot limited to methanol, ethanol, isopropanol, THF, water, diethylether, acetone, methyl tert-butyl ethers and other solvents known to theperson skilled in the art. Also advantageous is chromatographicenantiomer resolution with the aid of an optically active resolvingagent (for example dinitrobenzoylphenylglycine, cellulose triacetate orother derivatives of carbohydrates or chirally derivatised methacrylatepolymers immobilised on silica gel). Suitable eluents for this purposeare aqueous or alcoholic solvent mixtures, such as, for example,hexane/isopropanol/acetonitrile, for example in the ratio 82:15:3.

When discovering and developing therapeutic agents, the person skilledin the art attempts to optimize pharmacokinetic parameters whileretaining desirable in-vitro properties. It is reasonable to assume thatmany compounds with poor pharmacokinetic profiles are susceptible tooxidative metabolism. In-vitro liver microsomal assays currentlyavailable provide valuable information on the course of oxidativemetabolism of this type, which in turn permits the rational design ofdeuterated compounds of the formula (I) with improved stability throughresistance to such oxidative metabolism. Significant improvements in thepharmacokinetic profiles of compounds of the formula (I) are therebyobtained, and can be expressed quantitatively in terms of increases inthe in vivo half-life (t/2), concentration at maximum therapeutic effect(C_(max)), area under the dose response curve (AUC), and F; and in termsof reduced clearance, dose and materials costs.

A further aspect of the invention relates to the use of compoundsaccording to formula (I) and/or physiologically acceptable salts thereoffor inhibiting a glycosidase. Such use may be therapeutic ornon-therapeuic in character. The term “inhibition” denotes any reductionin glycosidase activity, which is based on the action of the specificinventive compounds capable to interact with the target glycosidase insuch a manner that makes recognition, binding and blocking possible. Itshall be understood that the compounds of the invention finally interactwith the target to unfold the effect. The compounds are characterized bysuch an appreciable affinity to at least one glycoside hydrolase whichensures a reliable binding and preferably a complete blocking ofglycosidase activity. More preferably, the substances are mono-specificin order to guarantee an exclusive and directed recognition with thechosen single glycosidase target. In the context of the presentinvention, the term “recognition”—without being limited thereto—relatesto any type of interaction between the specific compounds and thetarget, particularly covalent or non-covalent binding or association,such as a covalent bond, hydrophobic/hydrophilic interactions, van derWaals forces, ion pairs, hydrogen bonds, ligand-receptor interactions,and the like. Such association may also encompass the presence of othermolecules such as peptides, proteins or nucleotide sequences. Thepresent receptor/ligand-interaction is preferably characterized by highaffinity, high selectivity and minimal or even lacking cross-reactivityto other target molecules to exclude unhealthy and harmful impacts tothe treated subject.

In a preferred embodiment of the present invention, the glycosidasecomprises glycoside hydrolases, more preferably family 84 glycosidehydrolases, most preferablyO-glycoprotein-2-acetamido-2deoxy-3-D-glucopyranosidase (OGA), highlypreferably a mammalian O-GlcNAcase. It is particularly preferred thatthe compounds of formula (I) according to the invention selectively bindan O-GlcNAcase, e.g. thereby selectively inhibiting the cleavage of2-acetamido-2-deoxy-3-D-glucopyranoside (O-GlcNAc) while they do notsubstantially inhibit a lysosomal 1-hexosaminidase.

The compounds according to the invention preferably exhibit anadvantageous biological activity, which is easily demonstrated in enzymeactivity assays as described herein or known from prior art. In suchin-vitro assays, the compounds preferably exhibit and cause aninhibitory effect. IC₅₀ is the concentration of a compound that produces50% of the maximal inhibition for that compound. The glycosidase targetis especially half inhibited by the compounds described herein if theconcentration of the compounds amounts to less than 100 μM, preferablyless than 10 μM, more preferably less than 1 μM, most preferably lessthan 0.2 μM. Most preferably, compounds of Formula (I) exhibit an IC₅₀less than 0.02 μM.

A further aspect of the present invention relates to a method forinhibiting a glycosidase, wherein a system capable of expressing theglycosidase, particularly expressing said glycosidase, is contacted withat least one compound of formula (I) according to the invention and/orphysiologically acceptable salts thereof, under conditions such thatsaid glycosidase is inhibited. In a preferred embodiment of the method,the glycosidase is contacted with a compound selectively inhibitingO-GlcNAcase and more preferably having an IC₅₀ of less than 0.2 μM. Itis also preferred that the method is performed in-vitro and/or that themethod is not practiced on the human body. A cellular system ispreferred in the scope of the method. The cellular system is defined tobe any subject provided that the subject comprises cells. The cellrefers to any type of primary cells or genetically engineered cells,whether in the isolated status, in culture, as cell line, assembled intissue, organs or intact laboratory mammals, provided that they arecapable of expressing the glycosidase. It shall also be understood thatthe cell expresses the glycosidase as inherent pre-condition to put themethods of inhibition into practice. Although it is particularlypreferred that the cells are capable of expressing or do express theglycosidase, it shall not be excluded that glycosidase-deficient cellscan be used and the glycosidase is artificially added to the cellularsystem. The assay of the invention can be even completely performedin-vitro such that the cell is waived but a glycosidase is contactedwith at least one compound of formula (I) according to the inventionand/or physiologically acceptable salts thereof. Hence, an amount ofisolated glycosidase is provided in crude or purified form for thispurpose.

As discussed herein, the glycosidase-signaling pathways are relevant forvarious diseases, preferably neurodegenerative diseases, diabetes,cancer, cardiovascular diseases and stroke. Accordingly, the compoundsaccording to the invention are useful in the prophylaxis and/ortreatment of diseases that are dependent on the said signaling pathwaysby interaction with one or more of them. The present invention thereforerelates to the therapeutic and non-therapeutic use of compoundsaccording to the invention as inhibitors of the signaling pathwaysdescribed herein, preferably of the OGA-mediated signaling.

The method of the invention can be performed either in-vitro or in-vivo.The susceptibility of a particular cell to treatment with the compoundsaccording to the invention can be particularly determined by in-vitrotests, whether in the course of research or clinical application.Typically, a culture of the cell is combined with a compound accordingto the invention at various concentrations for a period of time which issufficient to allow the active agents to modulate glycosidase activity,usually between about one hour and one week. In-vitro treatment can becarried out using cultivated cells from any sample or cell line.

The host or patient can belong to any mammalian species, for example aprimate species, particularly humans; rodents, including mice, rats andhamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are ofinterest for experimental investigations, providing a model fortreatment of human disease.

For identification of a signal transduction pathway and for detection ofinteractions between various signal transduction pathways, variousscientists have developed suitable models or model systems, for examplecell culture models and models of transgenic animals. For thedetermination of certain stages in the signal transduction cascade,interacting compounds can be utilized in order to modulate the signal.The compounds according to the invention can also be used as reagentsfor testing OGA-dependent signal transduction pathways in animals and/orcell culture models or in the clinical diseases mentioned in thisapplication.

The use according to the previous paragraphs of the specification may beeither performed in-vitro or in-vivo models. The inhibition can bemonitored by the techniques described in the course of the presentspecification. The in-vitro use is preferably applied to samples ofhumans suffering from neurodegenerative diseases, diabetes, cancer,cardiovascular diseases and stroke. Testing of several specificcompounds and/or derivatives thereof makes the selection of that activeingredient possible that is best suited for the treatment of the humansubject. The in-vivo dose rate of the chosen derivative isadvantageously pre-adjusted to the glycosidase susceptibility and/orseverity of disease of the respective subject with regard to thein-vitro data. Therefore, the therapeutic efficacy is remarkablyenhanced. Moreover, the subsequent teaching of the present specificationconcerning the use of the compounds according to formula (I) and itsderivatives for the production of a medicament for the prophylactic ortherapeutic treatment and/or monitoring is considered as valid andapplicable without restrictions to the use of the compound for theinhibition of glycosidase activity, preferably OGA activity, ifexpedient.

A further aspect of the invention relates to a medicament comprising atleast one compound according to the invention and/or pharmaceuticallyusable derivatives, salts, solvates and stereoisomers thereof, includingmixtures thereof in all ratios. A “medicament” in the meaning of theinvention is any agent in the field of medicine, which comprises one ormore compounds of formula (I) or preparations thereof (e.g. apharmaceutical composition or pharmaceutical formulation) and can beused in prophylaxis, therapy, follow-up or aftercare of patients whosuffer from diseases, which are associated with OGA activity, in such away that a pathogenic modification of their overall condition or of thecondition of particular regions of the organism could establish at leasttemporarily.

Consequently, the invention also relates to a pharmaceutical compositioncomprising as active ingredient an effective amount of at least onecompound of formula (I) according to the invention and/orphysiologically acceptable salts thereof together with pharmaceuticallytolerable adjuvants and/or excipients.

In the meaning of the invention, an “adjuvant” denotes every substancethat enables, intensifies or modifies a specific response against theactive ingredient of the invention if administered simultaneously,contemporarily or sequentially. Known adjuvants for injection solutionsare, for example, aluminum compositions, such as aluminum hydroxide oraluminum phosphate, saponins, such as QS21, muramyldipeptide ormuramyltripeptide, proteins, such as gamma-interferon or TNF, M59,squalen or polyols.

Furthermore, the active ingredient may be administered alone or incombination with other treatments. A synergistic effect may be achievedby using more than one compound in the pharmaceutical composition, i.e.the compound of formula (I) is combined with at least another agent asactive ingredient, which is either another compound of formula (I) or acompound of different structural scaffold. The active ingredients can beused either simultaneously or sequentially. The present compounds aresuitable for combination with agents known to those of skill in the art(e.g., WO 2008/025170) and are useful with the compounds of theinvention.

In some embodiments, a compound according to the invention, or for useaccording to the invention, may be provided in combination with anyother active agents or pharmaceutical compositions where such combinedtherapy may be useful to modulate O-GlcNAcase activity, for example totreat neurodegenerative, inflammatory, cardiovascular, orimmunoregulatory diseases or any condition described herein. In someembodiments, a compound according to the invention, or for use accordingto the invention, may be provided in combination with one or more agentsuseful in the prevention or treatment of tauopathies and Alzheimer'sdisease. Examples of such agents may include, without limitation,

-   -   Acetylcholine esterase inhibitors (AChEIs) such as Aricept®        (Donepezil), Exelon® (Rivastigmine), Razadyne® (Razadyne ER®,        Reminyl®, Nivalin®, Galantamine), Cognex® (Tacrine), NMDA        antagonists such as memantine (Axura®, Ebixa®), Huperzine A,        Phenserine, Debio-9902 SR (ZT-1 SR), Zanapezil (TAK0147),        ganstigmine, NP7557, a7 nicotinic acetylcholine receptor        agonists, 5-HT6 receptor antagonists, M1 muscarinic        acetylcholine receptor agonists and positive allosteric        modulators, etc    -   Tau aggregation inhibitors such as methylene blue, etc    -   Agents blocking tau aggregation seeding and propagation such as        tau antibodies and tau vaccines, etc    -   Microtubule stabilizers such as AL-108, AL-208, paclitaxel, etc    -   Amyloid-β (Aβ) peptide lowering agents such as 1-secretase        (BACE-1) inhibitors, senile plaque-clearing biologics such as Aβ        antibodies and Aβ vaccines

The invention also relates to a set (kit) consisting of separate packsof an effective amount of a compound according to the invention and/orpharmaceutically acceptable salts, derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios, and aneffective amount of a further medicament active ingredient. The setcomprises suitable containers, such as boxes, individual bottles, bagsor ampoules. The set may, for example, comprise separate ampoules, eachcontaining an effective amount of a compound according to the inventionand/or pharmaceutically acceptable salts, derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios, and aneffective amount of a further medicament active ingredient in dissolvedor lyophilized form.

Pharmaceutical formulations can be adapted for administration via anydesired suitable method, for example by oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intra-dermal) methods. Such formulationscan be prepared using processes known in the pharmaceutical art by,e.g., combining the active ingredient with the excipient(s) oradjuvant(s).

The pharmaceutical composition of the invention is produced in a knownway using common solid or liquid carriers, diluents and/or additives andusual adjuvants for pharmaceutical engineering and with an appropriatedosage. The amount of excipient material that is combined with theactive ingredient to produce a single dosage form varies depending uponthe host treated and the particular mode of administration. Suitableexcipients include organic or inorganic substances that are suitable forthe different routes of administration, such as enteral (e.g. oral),parenteral or topical application, and which do not react with compoundsof formula (I) or salts thereof. Examples of suitable excipients arewater, vegetable oils, benzyl alcohols, alkylene glycols, polyethyleneglycols, glycerol triacetate, gelatin, carbohydrates, e.g. lactose orstarch, magnesium stearate, talc and petroleum jelly.

Pharmaceutical formulations adapted for oral administration can beadministered as separate units, such as, for example, capsules ortablets; powders or granules; solutions or suspensions in aqueous ornon-aqueous liquids; edible foams or foam foods; or oil-in-water liquidemulsions or water-in-oil liquid emulsions.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions comprisingantioxidants, buffers, bacteriostatics and solutes, by means of whichthe formulation is rendered isotonic with the blood of the recipient tobe treated; and aqueous and non-aqueous sterile suspensions, which maycomprise suspension media and thickeners. The formulations can beadministered in single-dose or multi-dose containers, for example sealedampoules and vials, and stored in freeze-dried (lyophilized) state, sothat only the addition of the sterile carrier liquid, for example waterfor injection purposes, immediately before use is necessary. Injectionsolutions and suspensions prepared in accordance with the recipe can beprepared from sterile powders, granules and tablets.

It goes without saying that, in addition to the above particularlymentioned constituents, the formulations may also comprise other agentsusual in the art with respect to the particular type of formulation;thus, for example, formulations which are suitable for oraladministration may comprise flavors.

In a preferred embodiment of the present invention, the pharmaceuticalcomposition is adapted for oral administration. The preparations can besterilized and/or can comprise auxiliaries, such as carrier proteins(e.g. serum albumin), lubricants, preservatives, stabilizers, fillers,chelating agents, antioxidants, solvents, bonding agents, suspendingagents, wetting agents, emulsifiers, salts (for influencing the osmoticpressure), buffer substances, colorants, flavorings and one or morefurther active substances, for example one or more vitamins. Additivesare well known in the art, and they are used in a variety offormulations.

Accordingly, the invention also relates to a pharmaceutical compositioncomprising as active ingredient an effective amount of at least onecompound of formula (I) according to the invention and/orphysiologically acceptable salts thereof together with pharmaceuticallytolerable adjuvants for oral administration, optionally in combinationwith at least another active pharmaceutical ingredient. The priorteaching of the present specification concerning administration routeand combination product, respectively, is valid and applicable withoutrestrictions to the combination of both features if expedient.

The terms “effective amount” or “effective dose” or “dose” areinterchangeably used herein and denote an amount of the pharmaceuticalcompound having a prophylactically or therapeutically relevant effect ona disease or pathological conditions, i.e. which causes in a tissue,system, animal or human a biological or medical response which is soughtor desired, for example, by a researcher or physician. A “prophylacticeffect” reduces the likelihood of developing a disease or even preventsthe onset of a disease. A “therapeutically relevant effect” relieves tosome extent one or more symptoms of a disease or returns to normalityeither partially or completely one or more physiological or biochemicalparameters associated with or causative of the disease or pathologicalconditions. In addition, the expression “therapeutically effectiveamount” denotes an amount which, compared with a corresponding subjectwho has not received this amount, has the following consequence:improved treatment, healing, prevention or elimination of a disease,syndrome, condition, complaint, disorder or side-effects or also thereduction in the advance of a disease, complaint or disorder. Theexpression “therapeutically effective amount” also encompasses theamounts which are effective for increasing normal physiologicalfunction.

The respective dose or dosage range for administering the pharmaceuticalcomposition according to the invention is sufficiently high in order toachieve the desired prophylactic or therapeutic effect of reducingsymptoms of the aforementioned diseases. It will be understood that thespecific dose level, frequency and period of administration to anyparticular human will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general state of health, gender, diet, time and route of administration,rate of excretion, drug combination and the severity of the particulardisease to which the specific therapy is applied. Using well-known meansand methods, the exact dose can be determined by one of skill in the artas a matter of routine experimentation. The prior teaching of thepresent specification is valid and applicable without restrictions tothe pharmaceutical composition comprising the compounds of formula (I)if expedient.

Pharmaceutical formulations can be administered in the form of dosageunits which comprise a predetermined amount of active ingredient perdosage unit. The concentration of the prophylactically ortherapeutically active ingredient in the formulation may vary from about0.1 to 100 wt %. Preferably, the compound of formula (I) or thepharmaceutically acceptable salts thereof are administered in doses ofapproximately 0.5 to 1000 mg, more preferably between 1 and 700 mg, mostpreferably 5 and 100 mg per dose unit. Generally, such a dose range isappropriate for total daily incorporation. In other terms, the dailydose is preferably between approximately 0.02 and 100 mg/kg of bodyweight. The specific dose for each patient depends, however, on a widevariety of factors as already described in the present specification(e.g. depending on the condition treated, the method of administrationand the age, weight and condition of the patient). Preferred dosage unitformulations are those which comprise a daily dose or part-dose, asindicated above, or a corresponding fraction thereof of an activeingredient. Furthermore, pharmaceutical formulations of this type can beprepared using a process which is generally known in the pharmaceuticalart.

Although a therapeutically effective amount of a compound according tothe invention has to be ultimately determined by the treating doctor orvet by considering a number of factors (e.g. the age and weight of theanimal, the precise condition that requires treatment, severity ofcondition, the nature of the formulation and the method ofadministration), an effective amount of a compound according to theinvention for the treatment of neurodegenerative diseases, for exampletauopathies and Alzheimer's disease, is generally in the range from 0.1to 100 mg/kg of body weight of the recipient (mammal) per day andparticularly typically in the range from 1 to 10 mg/kg of body weightper day. Thus, the actual amount per day for an adult mammal weighing 70kg is usually between 70 and 700 mg, where this amount can beadministered as a single dose per day or usually in a series ofpart-doses (such as, for example, two, three, four, five or six) perday, so that the total daily dose is the same. An effective amount of asalt or solvate or of a physiologically functional derivative thereofcan be determined as the fraction of the effective amount of thecompound according to the invention per se. It can be assumed thatsimilar doses are suitable for the treatment of other conditionsmentioned above.

The pharmaceutical composition of the invention can be employed asmedicament in human and veterinary medicine. According to the invention,the compounds of formula (I) and/or physiologically salts thereof aresuited for the prophylactic or therapeutic treatment and/or monitoringof diseases that are caused, mediated and/or propagated by OGA activity.It is particularly preferred that the diseases are neurodegenerativediseases, diabetes, cancer, cardiovascular diseases and stroke, morepreferably neurodegenerative diseases, most preferably one or moretauopathies, highly preferably Alzheimer's disease and dementia. Itshall be understood that the host of the compound is included in thepresent scope of protection according to the present invention.

Another aspect of the present invention relates to compounds of formula(I) according to the invention and/or physiologically acceptable saltsthereof for use in the prophylactic or therapeutic treatment and/ormonitoring of diseases that are caused, mediated and/or propagated byOGA activity. Another aspect of the invention concerns compounds offormula (I) according to the invention and/or physiologically acceptablesalts thereof for use in the prophylactic or therapeutic treatmentand/or monitoring of neurodegenerative diseases, diabetes, cancer,cardiovascular diseases and stroke. The prior teaching of the presentspecification concerning the compounds of formula (I), including anypreferred embodiment thereof, is valid and applicable withoutrestrictions to the compounds according to formula (I) and their saltsfor use in the prophylactic or therapeutic treatment and/or monitoringof neurodegenerative diseases, diabetes, cancer, cardiovascular diseasesand stroke.

Another aspect of the invention relates to a method for treating adisease that is caused, mediated and/or propagated by OGA activity,wherein an effective amount of at least one compound of formula (I)according to the invention and/or physiologically acceptable saltsthereof is administered to a mammal in need of such treatment. Anotheraspect of the invention relates to a method for treatingneurodegenerative diseases, diabetes, cancer, cardiovascular diseasesand stroke, preferably a tauopathy, wherein an effective amount of atleast one compound of formula (I) according to the invention and/orphysiologically acceptable salts thereof is administered to a mammal inneed of such treatment. The preferred treatment is an oraladministration. The prior teaching of the invention and its embodimentsis valid and applicable without restrictions to the methods of treatmentif expedient.

The neurodegenerative disease or condition is more preferably selectedfrom the group of one or more tauopathies and Alzheimer's disease,Amyotrophic lateral sclerosis (ALS), Amyotrophic lateral sclerosis withcognitive impairment (ALSci), Argyrophilic grain disease, Behaviorvariant frontotemporal dementia (bvFTD), Bluit disease, Corticobasaldegeneration (CBP), Dementia pugilistica, Dementia with Lewy Bodies,Diffuse neurofibrillary tangles with calcification, Down's syndrome,Familial British dementia, Familial Danish dementia, Frontotemporaldementia with parkinsonism linked to chromosome 17 (FTDP-17),Frontotemporal Lobar Degeneration (FTLD), Ganglioglioma, Gangliocytoma,Gerstmann-Straussler-Scheinker disease, Globular glial tauopathy,Guadeloupean parkinsonism, Hallevorden-Spatz disease (neurodegenerationwith brain iron accumulation type 1), Lead encephalopathy,Lipofuscinosis, Meningioangiomatosis, Multiple system atrophy, Myotonicdystrophy, Niemann-Pick disease (type C), Pallido-ponto-nigraldegeneration, Parkinson's disease, Parkinson's disease dementia (PDD),Parkinsonism-dementia complex of Guam, Pick's disease (PiD),Postencephalitic parkinsonism (PEP), Primary progressive aphasia, Priondiseases (including Creutzfeldt-Jakob Disease (GJD), VariantCreutzfeldt-Jakob Disease (vCJD), Fatal Familial Insomnia, Kuru,Progressive supercortical gliosis, Progressive supranuclear palsy (PSP),Pure Autonomic Failure, Richardson's syndrome, Subacute sclerosingpanencephalitis, Tangle-only dementia, Tuberous Sclerosis, Huntington'sdisease. Most preferred are one ore more tauopathies and Alzheimer'sdisease.

The invention also relates to the use of compounds according to formula(I) and/or physiologically acceptable salts thereof for the prophylacticor therapeutic treatment and/or monitoring of diseases that are caused,mediated and/or propagated by OGA activity. Furthermore, the inventionrelates to the use of compounds according to formula (I) and/orphysiologically acceptable salts thereof for the production of amedicament for the prophylactic or therapeutic treatment and/ormonitoring of diseases that are caused, mediated and/or propagated byOGA activity. Compounds of formula (I) and/or a physiologicallyacceptable salt thereof can furthermore be employed as intermediate forthe preparation of further medicament active ingredients. The medicamentis preferably prepared in a non-chemical manner, e.g. by combining theactive ingredient with at least one solid, fluid and/or semi-fluidcarrier or excipient, and optionally in conjunction with a single ormore other active substances in an appropriate dosage form.

The compounds of formula (I) according to the invention can beadministered before or following an onset of disease once or severaltimes acting as therapy. The aforementioned compounds and medicalproducts of the inventive use are particularly used for the therapeutictreatment. A therapeutically relevant effect relieves to some extent oneor more symptoms of a disorder, or returns to normality, eitherpartially or completely, one or more physiological or biochemicalparameters associated with or causative of a disease or pathologicalcondition. Monitoring is considered as a kind of treatment provided thatthe compounds are administered in distinct intervals, e.g. in order tobooster the response and eradicate the pathogens and/or symptoms of thedisease completely. Either the identical compound or different compoundscan be applied. The medicament can also be used to reducing thelikelihood of developing a disorder or even prevent the initiation ofdisorders associated with OGA activity in advance or to treat thearising and continuing symptoms. The disorders as concerned by theinvention are preferably neurodegenerative diseases, diabetes, cancer,cardiovascular diseases and stroke.

In the meaning of the invention, prophylactic treatment is advisable ifthe subject possesses any preconditions for the aforementionedphysiological or pathological conditions, such as a familialdisposition, a genetic defect, or a previously passed disease.

In the scope of the present invention, compounds of formula (I) areprovided for the first time. The low molecular weight compounds of theinvention are strong and selective glycosidase inhibitors with improvedpassive permeability. The compounds of formula (I) have been shown to becompetitive with PUGNAc, a known OGA inhibitor that binds in thesubstrate pocket. The endogenous substrate is an O-GlcNAcylated protein.O-GlcNAcylation of nuclear and cytoplasmic proteins is one of the mostcommon post-translational modifications in animals and plants. 0-GlcNAccycling modulates a number of cellular processes, and evidence ismounting that dysregulation of O-GlcNAcylation plays a role in theetiology of several diseases, including tauopathies and Alzheimer'sdisease. O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) are the twoenzymes that regulate O-GlcNAc cycling. Emerging data suggest thatinhibitors that block OGA may help maintain healthy O-GlcNAc levels intauopathies and Alzheimer's disease patients and thereby inhibit theformation of neurofibrillary tangles. Hence, the current inventioncomprises the use of compounds of formula (I) in the regulation,modulation and/or inhibition of the glycosidase signal cascade, whichcan be advantageously applied as research tool, for diagnosis and/or intreatment of any disorders that are responsive to OGA signaling andinhibition.

The low molecular weight inhibitors can be applied either themselvesand/or in combination with physical measurements for diagnostics oftreatment effectiveness. Medicaments and pharmaceutical compositionscontaining said compounds and the use of said compounds to treatglycosidase-mediated conditions is a promising, novel approach for abroad spectrum of therapies causing a direct and immediate improvementin the state of health, whether in man and animal. The impact is ofspecial benefit to efficiently combat tauopathies and Alzheimer'sdisease, either alone or in combination with other neurodegenerativetreatments.

Due to the surprisingly appreciable inhibitory activity on OGA, alongwith passive permeability, the compounds of the invention can beadvantageously administered at lower doses compared to other less potentor selective inhibitors of prior art while still achieving equivalent oreven superior desired biological effects. In addition, such a dosereduction advantageously leads to less or even no medicinal adverseeffects.

The compounds of formula (I), their salts, isomers, tautomers,enantiomeric forms, diastereomers, racemates, derivatives, prodrugsand/or metabolites are characterized by a high specificity andstability, low manufacturing costs and convenient handling. Thesefeatures form the basis for a reproducible action, wherein the lack ofcross-reactivity is included, and for a reliable and safe interactionwith the target structure.

All the references cited herein are incorporated by reference in thedisclosure of the invention hereby.

The techniques that are essential according to the invention aredescribed in detail in the specification. Other techniques which are notdescribed in detail correspond to known standard methods that are wellknown to a person skilled in the art, or the techniques are described inmore detail in cited references, patent applications or standardliterature. Although methods and materials similar or equivalent tothose described herein can be used in the practice or testing of thepresent invention, suitable examples are described below. The followingexamples are provided by way of illustration and not by way oflimitation. Within the examples, standard reagents and buffers that arefree from contaminating activities (whenever practical) are used. Theexamples are particularly to be construed such that they are not limitedto the explicitly demonstrated combinations of features, but theexemplified features may be unrestrictedly combined again provided thatthe technical problem of the invention is solved. Similarly, thefeatures of any claim can be combined with the features of one or moreother claims.

EXPERIMENTAL PART

The compounds according to Formula (I) can be prepared from readilyavailable starting materials by several synthetic approaches, using bothsolution-phase and solid-phase chemistry protocols or mixed solution andsolid phase protocols. Examples of synthetic pathways are describedbelow in the examples. All reported yields are non optimized yields.Unless otherwise stated, compounds of Formula (I) and related formulaeobtained as a racemic mixture can be separated to provide anenantiomerically enriched mixture or a pure enantiomer.

The commercially available starting materials used in the followingexperimental description were purchased from Aldrich, Sigma, ACROS,ABCR, Combi-Blocks, Matrix, Apollo scientific, Alfa Aesar, etc. unlessotherwise reported.

The HPLC, MS and NMR data provided in the examples described below areobtained as followed:

¹H NMR analyses were carried out using BRUKER NMR, model AV-II andAV-III 400 MHz FT-NMR. Residual signal of deuterated solvent was used asinternal reference. Chemical shifts (δ) are reported in ppm in relativeto the residual solvent signal (δ=2.50 for ¹H NMR in DMSO-d₆, and 7.26in CDCl₃). s (singlet), d (doublet), t (triplet), q (quadruplet), br(broad), quint (quintuplet).

LCMS Analysis Condition:

Instrument Name:

Agilent Technologies 1290 infinity 11.

Method A:

Method: A-0.1% TFA in H₂O, B-0.1% TFA in ACN; flow rate: 2.0 mL/min;column: XBridge C8 (50×4.6 mm, 3.5 μm), +ve mode

Method B:

Method: A-10 mM NH₄HCO₃ in H₂O, B-ACN; flow rate: 1.0 mL/min; column:XBridge C8 (50×4.6 mm, 3.5 μm), +ve mode

HPLC Analysis Condition:

Instrument Name:

Agilent 1200 Series instruments as followed using % with UV detection(maxplot).

Method A:

Method: A-0.1% TFA in H₂O, B-0.1% TFA in ACN; flow rate: 2.0 mL/min;column: XBridge C8 (50×4.6 mm, 3.5 μm).

Method B:

Method: A-10 mM NH₄HCO₃ in H₂O, B-ACN; flow rate: 1.0 mL/min; column:XBridge C8 (50×4.6 mm, 3.5 μm).

Chiral SFC Analysis Condition:

Instrument Name:

THAR-SFC 80 and THAR-SFC 200 (analytical) and Pic SFC 10-150 Ratiobetween CO₂ and co-solvent is ranging between 50:50 and 90:10

Method A:

Mobile Phase: 20 mM Ammonia in Methanol flow: 4 mL/min; COLUMN: Lux C3(250×4.6) mm, 5 μm

Method B:

Mobile Phase: 0.5% Isopropyl Amine in Methanol, 3 mL/min column:Chiracel OD-H (250×4.6) mm, 5 μm

Method C:

Mobile Phase: 20 mmol ammonia in Methanol, 3 mL/min column: ChiracelOJ-H (250×4.6) mm, 5 μm

Chiral Preparative SFC Analysis Condition:

Instrument Name:

THAR-SFC 80, THAR-SFC 200 and Pic SFC 10-150

Ratio between CO₂ and co-solvent is ranging between 50:50 and 90:10

Method A:

Co-solvent: 20 mM Ammonia in Methanol flow: 5 mL/min; COLUMN: Lux C3(250×30) mm, 5 μm

Method B:

Co-solvent: 0.5% Isopropyl Amine in Methanol, 5 mL/min column: ChiracelOD-H (250×30) mm, 5 μm

Method C:

Co-solvent: 20 mmol ammonia in Methanol, 5 mL/min column: Chiracel OJ-H(250×30) mm, 5 μm

The microwave chemistry was performed on a single mode microwave reactorInitiator™ Sixty from Biotage.

General flash chromatography conditions used for the purification ofintermediates or compounds of Formula I: silica gel 230-400 mesh;gradients used as elutent: 10 to 80% EtOAc in petroleum ether or 1 to15% MeOH in DCM

Intermediate 1: 6-(1-chloroethyl)-2-methyl-2,3-dihydrobenzofuran

Step 1: 1-(3-(allyloxy)phenyl)ethan-1-one

To a stirred solution of 1-(3-hydroxyphenyl)ethan-1-one (25 g, 18.36mol) in dry acetone (60 mL), potassium carbonate (81.2 g, 58.75 mol) wasadded at RT and the reaction mixture was stirred RT for 10 min. Allylbromide (24 ml, 27.54 mol) was then added and the resulting mixture wasrefluxed for 6 h. Completion of the reaction was monitored by TLC, thereaction mixture was then filtered. The resulting filtrate wasconcentrated under vacuum to afford the title compound. Yield: 93% (30g, brown liquid). ¹H NMR (400 MHz, CDCl₃): δ 7.56 (d, J=8.0 Hz, 1H),7.52 (t, J=2.0 Hz, 1H) 7.39 (t, J=7.6 Hz, 1H), 7.15 (dd, J=8.2, 2.8 Hz,1H), 6.12-6.11 (m, 1H), 5.46 (dd, J=14.2, 1.2 Hz, 1H), 5.33 (dd, J=10.6,1.2 Hz, 1H), 4.63-4.61 (m, 2H), 2.62 (s, 3H).

Step 2: Mixture of 1-(4-allyl-3-hydroxyphenyl) ethan-1-one and1-(2-allyl-3-hydroxyphenyl) ethan-1-one

A solution of 1-(3-(allyloxy)phenyl)ethan-1-one (5.0 g, 36.7 mmol) inpolyethylene glycol (10 mL) was stirred at 250° C. for 2 h undermicrowave irradiation. After completion of the reaction (monitored byTLC), water (10 mL) was added to the resulting mixture and the aqueouslayer was extracted with EtOAc (2×50 mL). The combined organic layer wasdried over anhydrous Na₂SO₄ and concentrated under vacuum. The resultingcrude material was purified by flash chromatography (Biotage Isolera,eluent: 30-50% EtOAc in hexane) to afford the title compound. Based onthe LCMS analysis, the ratio between the two regio-isomers was 1.5:1.The mixture of regioisomer was forwarded to the next step as such.Yield: 57% (17 g, pale brown liquid). ¹H NMR (400 MHz, CDCl₃): δ7.50-7.49 (m, 1H), 7.24-7.20 (m, 2H), 7.01-6.99 (m, 1H), 6.08-6.02 (m,1H), 5.19-5.08 (m, 1H), 4.15 (s, H), 3.49 (d, J=6.4 Hz, 2H), 2.08 (s,3H). LCMS: (Method B) 175.2 (M−H), Rt 1: 4.9 min, 53.8%; Rt 2: 2.5 min,34.3% (Max).

Step 3: 1-(2-methyl-2,3-dihydrobenzofuran-6-yl)ethan-1-one (Isomer A)and 1-(2-methyl-2, 3-dihydrobenzofuran-4-yl)ethan-1-one (Isomer B)

To a stirred solution of 1-(4-allyl-3-hydroxyphenyl) ethan-1-one and1-(2-allyl-3-hydroxyphenyl) ethan-1-one (17 g, 96.4 mmol) in dry DCM (60mL), zirconium chloride (44 g, 0.19 mol) was added at RT and thereaction mixture was stirred at RT for 12 h. The reaction mixture wasthen filtered and the filtrate was concentrated under vacuum. Theresulting crude material was purified by flash chromatography (BiotageIsolera, run time: 1.5 h (long run), eluent: 4% EtOAc in hexane) to givetitle compound to afford isomer A and isomer B.

Analysis of isomer A: Yield: 6.0% (1.5 g, brown liquid). ¹H NMR (400MHz, CDCl₃): δ 7.49 (t, J=9.2 Hz, 1H), 7.33 (d, J=1.2 Hz, 1H), 7.24 (d,J=7.6 Hz, 1H), 5.03-5.01 (m, 1H), 3.41-3.35 (m, 1H), 2.90-2.84 (m, 1H),2.57 (t, J=1.2 Hz, 3H), 1.50 (d, J=6.4 Hz, 3H). HPLC: (Method A) Rt. 3.5min, 99.4% (Max).

Analysis of isomer B: ¹H NMR (400 MHz, DMSO-d₆): δ 7.37 (d, J=7.6 Hz,1H), 7.24-7.18 (m, 1H), 6.95 (d, J=7.6 Hz, 1H), 5.00-4.94 (m, 1H),3.72-3.65 (m, 1H), 3.18-3.11 (m, 1H), 2.60 (s, 3H), 1.49-1.47 (m, 3H).LCMS: (Method A) 177.3 (M+H), Rt. 3.7 min, 74.5% (Max).

Step 4: 1-(2-methyl-2,3-dihydrobenzofuran-6-yl)ethan-1-ol

To a stirred solution of 1-(2, 3-dihydrobenzofuran-6-yl)ethan-1-one(0.32 g, 1.82 mmol) in methanol (7.4 mL, 20V) at 0° C., NaBH₄ (0.14 mL,3.60 mmol) was added and the reaction mixture was stirred at RT for 60min. After completion (monitored by TLC), the reaction mixture wasquenched with ice-cold water (5 mL) and the aqueous layer was extractedwith DCM (2×10 mL). The combined organic layer was washed with brine (5mL), dried over Na₂SO₄ and concentrated under vacuum to afford the titlecompound. Yield: 82.5% (crude, 0.25 g, brown liquid). ¹H NMR (400 MHz,CDCl₃): δ 7.12 (d, J=7.4 Hz, 1H), 6.85 (d, J=7.4 Hz, 1H), 6.80 (s, 1H),4.97-4.95 (m, 1H), 4.87-4.86 (m, 1H), 3.33-3.31 (m, 1H), 2.83-2.78 (m,1H), 1.48-1.47 (m, 6H). LCMS: (Method A) 161.2 (M−H₂O+H), Rt. 3.1 min,99.7% (Max).

Step 5: 6-(1-chloroethyl)-2-methyl-2, 3-dihydrobenzofuran

To a stirred solution of1-(2-methyl-2,3-dihydrobenzofuran-6-yl)ethan-1-ol (0.25 mg, 1.90 mmol)in DCM (10 mL), SOCl₂ (0.5 mL, 5.8 mmol) was added at 0° C., and theresulting mixture was stirred at RT for 2 hr. After completion of thereaction (monitored by TLC), the reaction mixture was concentrated undervacuum and the resulting crude was co-distilled with DCM (2×10 mL) toafford the title compound. The resulting solid was used for the nextstep without further purification. Yield: 80% (275 mg, pale brown gummysolid). ¹H NMR (300 MHz, CDCl₃): δ 7.13 (d, J=7.5 Hz, 1H), 6.85 (m, 2H),5.09-4.90 (m, 2H), 3.35-3.27 (m, 1H), 2.85-2.77 (m, 1H), 1.83 (d, J=8.00Hz, 3H), 1.46 (d, J=6.3 Hz, 3H). LCMS: (Method A) 161.2 (M−HCl+H), Rt.4.3 min 65.2% (Max).

Intermediate 2: N-(5-(piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamidehydrochloride

Step 1: tert-Butyl4-(5-amino-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate

To a stirred solution of 2-amino 5-bromo-1, 3, 4-thiadiazole (10.0 g,55.5 mmol) in dry DMF (100 mL), K₂CO₃ (15.3 g, 111.1 mmol) and 1-bocpiperazine (12.4 g, 66.65 mmol) were added at 0° C. and the reactionmixture was stirred at 80° C. overnight. Completion of the reaction wasmonitored by TLC, then the reaction mixture was concentrated undervacuum. To the resulting mixture DCM (200 mL) was added, the organiclayer was washed with water (100 mL), brine (100 mL) and dried overanhydrous Na₂SO₄. Then the organic layer was concentrated under vacuumand the resulting crude material was purified by flash chromatography(Biotage Isolera, eluent: 2-5% methanol in DCM) to afford the titlecompound. Yield: 76% (12 g, pale brown solid). ¹H NMR (400 MHz,DMSO-d₆): δ 6.51 (s, 2H), 3.39 (d, J=6.9 Hz, 4H), 3.19 (d, J=7.7 Hz,4H), 1.39 (s, 9H). LCMS: (Method A) 286.1 (M+H), Rt. 2.7 min, 97.6%(Max).

Step 2: tert-Butyl4-(5-acetamido-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate

To a stirred solution of tert-butyl4-(5-amino-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (12.0 g, 42.09mmol) in pyridine (120 mL), acetic anhydride (5.1 g, 50.5 mmol) wasadded at 0° C. and the reaction mixture was stirred at 50° C. overnight.After completion of the reaction (monitored by TLC), the reactionmixture was concentrated under vacuum and the obtained material wastriturated with diethyl ether (100 mL). The resulting crude material wasfiltered, dried under vacuum and forwarded to the next step as suchwithout any further purification. Yield: 87% (12 g, off white solid). ¹HNMR (400 MHz, DMSO-d₆): δ 12.07 (bs, 1H), 3.45-3.34 (m, 8H), 2.11 (s,3H), 1.42 (s, 9H). LCMS: (Method A) 328.0 (M+H), Rt. 3.1 min, 86.3%(Max).

Step 3: N-(5-(Piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamidehydrochloride

To a stirred solution of tert-butyl4-(5-acetamido-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (12.0 g)in dry 1, 4-dioxane (100 mL) at 0° C., HCl solution in dioxane (100 mL,4M) was added dropwise and the reaction mixture was stirred at RT for 3h. After completion of the reaction (monitored by TLC), the reactionmixture was concentrated under vacuum and the obtained material wastriturated with diethyl ether (50 mL). The resulting material was driedunder vacuum and forwarded to the next step as such. Yield: 93% (9 g,white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 12.07 (bs, 1H), 3.67 (s, 4H),3.21 (s, 4H), 2.13 (s, 3H). LCMS: (Method A) 228.0 (M+H), Rt. 0.7 min,85.3% (Max).

Intermediate 3: 2-(piperazin-1-yl)-7, 8-dihydropyrido[4, 3-d]pyrimidin-5(6H)-one hydrochloride

Step 1: tert-butyl 4-carbamimidoylpiperazine-1-carboxylate

To the stirred solution of tert-butyl piperazine-1-carboxylate (20 g,107.5 mmol) in DMF (200 mL), DIPEA (19.0 mL, 107.5 mmol) followed by1H-pyrazole-1-carboxamide hydrochloride (15.76 g, 107.5 mmol) were addedat RT and the reaction mixture was stirred at 60° C. for 6 h. Aftercompletion of the reaction (monitored by TLC), the reaction mixture wascooled at 0° C., MTBE (200 mL) was added and the reaction mixture wasstirred for 1 h. The resulting solid material was washed with MTBE (2×50mL), Et₂O (50 mL) and dried under vacuum to afford the title compound.Yield: 83% (20 g, white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.71-7.69(m, 3H), 3.44-3.34 (m, 8H), 1.42 (s, 9H).

Step 2: 3-((dimethylamino) methylene) piperidine-2,4-dione

To a stirred solution of 2, 4-piperidinedione (10 g, 88.4 mmol) in ACN(100 mL), N, N-dimethyl formamide dimethylacetal (23.5 mL, 176.8 mmol)was added and the reaction mixture was stirred at RT overnight. Aftercompletion of the reaction (monitored by TLC), the resulting reactionmixture was evaporated under vacuum, the obtained crude material wastriturated with diethyl ether (2×20 mL) and dried to afford the titlecompound. Yield: 92% (13.6 g, brown solid). ¹H NMR (300 MHz, DMSO-d₆): δ7.83 (s, 1H), 7.15 (s, 1H), 3.29 (s, 3H), 3.16 (t, J=6.3 Hz, 2H), 3.06(s, 3H), 2.30 (t, J=6.3 Hz, 2H). LCMS: (Method A) 169.2 (M+H), Rt. 1.2min, 90.4%.

Step 3:tert-butyl-4-(5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)piperazine-1-carboxylate

To a stirred solution of tert-butyl4-carbamimidoylpiperazine-1-carboxylate (18.32 g, 80.2 mmol) and3-((dimethylamino) methylene) piperidine-2,4-dione (13.5 g, 80.2 mmol)in EtOH (135 mL), K₂CO₃ (26.66 g, 193.0 mmol) was added and the reactionmixture was heated at 80° C. for 6 h. After completion of the reaction(monitored by TLC), the reaction mixture was cooled to RT and theobtained precipitate was collected by filtration. The resulting crudematerial was washed with EtOH (30 mL), water (3×30 mL), diethyl ether(2×20 mL) and dried under vacuum to afford the title compound. Yield:85% (22.7 g, white solid). ¹H NMR (300 MHz, DMSO-d₆): 8.63 (s, 1H), 7.74(s, 1H), 3.85-3.81 (m, 4H), 3.41-3.39 (m, 6H), 2.82 (t, J=6.3 Hz, 2H),1.43 (s, 9H). LCMS: (Method A) 334.2 (M+H), Rt. 3.4 min, 99.4% (Max).

Step 4: 2-(piperazin-1-yl)-7, 8-dihydropyrido[4, 3-d]pyrimidin-5(6H)-one hydrochloride

To a stirred solution oftert-butyl-4-(5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)piperazine-1-carboxylate(22 g, 66.0 mmol) in 1, 4-dioxane (66 mL) at 0° C., HCl solution indioxane (110 mL, 5V, 4M) was added dropwise and the reaction mixture wasstirred at RT for 4 h. After completion of the reaction (monitored byTLC), the reaction mixture was filtered and the obtained solid waswashed with EtOAc (3×30 mL). The resulting material was dried undervacuum to afford the title compound which was forwarded to the next stepas such. Yield: 94% (19 g, white solid). LCMS: (Method A) 234.2 (M+H),Rt. 0.6 min, 94.8% (Max).

Intermediate 4: (2R)-6-(1-chloroethyl)-2-methyl-2,3-dihydrobenzofuran

Step 1: (R)-1-(trityloxy)propan-2-ol

To a stirred solution of (R)-propane-1, 2-diol (15.0 g, 0.19 mol) in DCM(300 mL) at 0° C., TEA (44.37 mL, 0.31 mol) and tritylchloride (56 g,0.20 mol) in DCM (100 mL) were added slowly under nitrogen atmosphereand the reaction mixture was stirred at RT overnight. After completionof the reaction (monitored by TLC), the reaction mixture was quenchedwith sat. NH₄Cl (150 mL) and the aqueous layer was extracted with DCM(2×100 mL). The combined organic layer was washed with water (100 mL),brine (100 mL), dried over anhydrous Na₂SO₄ and evaporated under vacuumto afford the title compound. Yield: 84% (52.09 g, pale yellow gummyliquid). ¹H NMR (400 MHz, CDCl₃): δ 7.49-7.42 (m, 6H), 7.35-7.29 (m,6H), 7.28-7.25 (m, 3H), 4.03-3.98 (m, 1H), 3.16 (dd, J=9.2, 3.2 Hz, 1H),3.02 (dd, J=9.2, 8.0 Hz, 1H), 2.39 (s, 1H), 1.09 (d, J=6.4 Hz, 3H).

Step 2: (R)-((2-(2,5-dibromophenoxy)propoxy)methanetriyl)tribenzene

To a stirred solution of 1, 4-dibromo-2-fluorobenzene (32 g, 0.13 mmol)and (R)-1-(trityloxy)propan-2-ol (44.24 g, 0.14 mmol) in THF (300 mL),KOtBu (56.8 g, 0.5 mmol) was added batchwise over 25 min at 5° C. andthe reaction mixture was heated at 70° C. overnight. After completion ofthe reaction (monitored by TLC), the mixture was cooled to RT, dilutedwith water (150 mL) and the aqueous layer was extracted with EtOAc(2×150 mL). The combined organic layer was washed with water (100 mL),brine (100 mL), dried over anhydrous Na₂SO₄ and concentrated undervacuum. The resulting crude material was purified by flashchromatography (Biotage Isolera, eluent: 6% EtOAc in hexane) to affordthe title compound. Yield: 65% (45.3 g, off white solid). ¹H NMR (400MHz, CDCl₃): δ 7.48-7.41 (m, 7H), 7.36-7.12 (m, 11H), 4.60-4.57 (m, 1H),3.46 (dd, J=10.0, 6.4 Hz, 1H), 3.17 (dd, J=10.0, 6.2 Hz, 1H), 1.33 (d,J=6.4, Hz, 3H).

Step 3: (R)-2-(2, 5-dibromophenoxy) propan-1-ol

To a stirred solution of(R)-((2-(2,5-dibromophenoxy)propoxy)methanetriyl)tribenzene (25 g, 32.54mmol) in dry DCM (250 mL), 10% TFA in DCM (50 mL) was added dropwise at0° C. and the reaction mixture was stirred at RT for 1 h. Aftercompletion of the reaction (monitored by TLC), the mixture was cooled to0° C., quenched with sat. NaHCO₃ and the aqueous layer was extractedwith DCM (2×150 mL). The combined organic layer was washed with brine(30 mL), dried over anhydrous Na₂SO₄ and concentrated under vacuum. Theresulting crude material was purified by flash chromatography (BiotageIsolera, eluent: 18% EtOAc in hexane) to afford the title compound.Yield: 32% (7.5 g, pale brown gummy oil). ¹H NMR (400 MHz, CDCl₃): δ7.41 (d, J=8.4 Hz, 1H), 7.12 (s, 1H), 7.02 (d, J=8.8 Hz, 1H), 4.52-4.48(m, 1H), 3.79 (m, 2H), 1.36 (d, J=6.4 Hz, 3H). HPLC: (Method A), Rt. 4.2min, 99.7% (Max). Chiral SFC: (Method D), Rt 2.7 min, 96.6%.

Step 4: (R)-1, 4-dibromo-2-((1-bromopropan-2-yl)oxy)benzene

To a stirred solution of (R)-2-(2, 5-dibromophenoxy) propan-1-ol (7.0 g,22.5 mmol) in DCM (70 mL), TPP (7.09 g, 27.09 mmol) and CBr₄ (8.98 g,27.09 mmol) were added under nitrogen atmosphere at 0° C. and thereaction mixture was stirred for 2 h at RT. After completion of thereaction (monitored by TLC), the mixture was evaporated under vacuum andthe resulting crude material was purified by flash chromatography(Biotage Isolera, eluent: 10% EtOAc in hexane) to afford the titlecompound. Yield: 62% (5.1 g, pale brown gummy solid). ¹H NMR (400 MHz,CDCl₃): δ 7.43 (dd, J=8.4, 1.6 Hz, 1H), 7.09 (d, J=2.0 Hz, 1H),7.09-7.03 (m, 1H), 4.58 (m, 1H), 3.61 (dd, J=10.6, 5.2 Hz, 1H), 3.50(dd, J=8.4, 1.2 Hz, 1H), 1.53 (d, J=6.0 Hz, 3H).

Step 5: (R)-2-methyl-2, 3-dihydrobenzofuran-6-carbaldehyde

To a stirred solution of (R)-1,4-dibromo-2-((1-bromopropan-2-yl)oxy)benzene (4.8 g, 0.013 mol) in dryTHF (40 mL) under nitrogen atmosphere, n-butyl lithium (8.8 mL, 0.014mol, 1.6 M in hexane) was added slowly over 10 min at −78° C. andstirred for 1 h. Second lot of n-butyl lithium (8.8 mL, 0.014 mol, 1.6 Min hexane) was added slowly over 10 min at −78° C. and stirring wascontinued for another 1 h. Then DMF (1.0 mL, 12.8 mmol) was addedslowly, maintained for 45 min at −78° C. and completion of reaction wasmonitored by TLC. The reaction mixture was then warmed to 10° C.,quenched with sat.NH₄Cl solution (20 mL) and the aqueous layer wasextracted with EtOAc (2×25 mL). The combined organic layer was washedwith water (10 mL), brine solution (5 mL), dried over anhydrous Na₂SO₄and evaporated under vacuum. The resulting crude material was purifiedby flash chromatography (Biotage Isolera, eluent: 15-20% EtOAc inhexane) to afford the title compound. Yield: 78% (1.7 g, brown gummyoil). ¹H NMR (400 MHz, CDCl₃): δ 9.92 (s, 1H), 7.39 (dd, J=7.4, 1.2 Hz,1H), 7.31 (d, J=7.8 Hz, 1H), 7.24 (s, 1H), 5.04-4.99 (m, 1H), 3.40 (dd,J=16.4, 8.8 Hz, 1H), 2.89 (dd, J=14.0, 2.8 Hz, 1H), 1.51 (d, J=6.4 Hz,3H). LCMS: (Method A) 163.1 (M+H), Rt. 3.4 min, 64.6% (Max).

Step 6: 1-((R)-2-methyl-2, 3-dihydrobenzofuran-6-yl)ethan-1-ol

To a stirred solution of (R)-2-methyl-2,3-dihydrobenzofuran-6-carbaldehyde (1.6 g, 9.80 mmol) in dry THF (10 mL)under nitrogen atmosphere, methyl magnesium chloride solution (4.9 mL,0.02 mol, 3 M in THF) was added slowly over 10 min at 0° C. and stirredfor 2 h. Completion of the reaction was monitored by TLC, then thereaction mixture quenched by sat.NH₄Cl solution (10 mL) and the aqueouslayer was extracted with EtOAc (2×15 mL). The combined organic layer waswashed with water (5 mL), brine solution (2 mL), dried over anhydrousNa₂SO₄ and evaporated under vacuum. The resulting crude material waspurified by flash chromatography (Biotage Isolera, eluent: 18% EtOAc inpet ether) to afford the title compound. Yield: 91% (1.0 g, pale yellowliquid). ¹H NMR (400 MHz, CDCl₃): δ 7.14 (d, J=7.6 Hz, 1H), 6.86 (dd,J=7.4, 1.6 Hz, 1H), 6.81 (s, 1H), 4.98-4.92 (m, 1H), 4.86 (q, J=6.4 Hz,1H), 3.31 (dd, J=15.2, 8.8 Hz 1H), 2.81 (dd, J=15.6, 7.6 Hz, 1H), 1.52(s, 3H), 1.51 (d, J=6.8 Hz, 3H). LCMS: (Method A) 161.0 (M−H₂O+H), Rt2.2 min, 81.1% (Max).

Step 7: (2R)-6-(1-chloroethyl)-2-methyl-2, 3-dihydrobenzofuran

To a stirred solution of 1-((R)-2-methyl-2,3-dihydrobenzofuran-6-yl)ethan-1-ol (0.5 g, 2.80 mmol) in DCM (20 mL),SOCl₂ (0.48 mL, 4.79 mmol) was added 0° C. and the reaction mixture wasstirred at RT for 1 h. After completion of reaction (monitored by TLC),the mixture was concentrated under vacuum and the resulting crudematerial was co-distilled with dry DCM (2×500 mL) to afford the titlecompound. Yield: 98% (crude, 500 mg, brown gummy oil). LCMS: (Method A)161.0 (M−HCl+H), Rt. 4.9 min, 35.9% (Max).

Intermediate 5: (2S)-6-(1-chloroethyl)-2-methyl-2,3-dihydrobenzofuran

Step 1: (S)-1-(trityloxy)propan-2-ol

To a stirred solution of (S)-propane-1, 2-diol (10 g, 0.13 mol) in DCM(200 mL), TEA (30 ml 0.21 mol) and tritylchloride (36.63 g, 0.13 mol) inDCM (100 mL) were added slowly at 0° C. under nitrogen atmosphere andthe reaction mixture was stirred at RT overnight. Completion of thereaction was monitored by TLC, then the reaction mixture was quenchedwith sat. NH₄Cl (150 mL) and the aqueous layer was extracted with DCM(2×100 mL). The combined organic layer was washed with water (100 mL),brine (50 mL), dried over anhydrous Na₂SO₄ and concentrated under vacuumto afford the title compound. Yield: 71% (30 g, pale yellow gummy oil).¹H NMR (400 MHz, CDCl₃): δ 7.49-7.463 (m, 6H), 7.39-7.28 (m, 6H),7.28-7.23 (m, 3H), 4.04-3.99 (m, 1H), 3.18 (dd, J=9.4, 3.6 Hz, 1H),3.06-3.00 (m, 1H), 2.46 (d, J=3.2 Hz 1H), 1.14 (d, J=6.4 Hz, 3H). HPLC:(Method A), Rt. 5.5 min, 85.1% (Max).

Step 2: (S)-((2-(2, 5-dibromophenoxy)propoxy)methanetriyl)tribenzene

To a stirred solution of 1, 4-dibromo-2-fluorobenzene (22 g, 0.09 mol)and (S)-1-(trityloxy)propan-2-ol (27.65 g, 0.09 mol) in THF (300 mL),K^(t)OBu (21.48 g, 0.191 mol) was added batchwise over 25 min at 5° C.and the reaction mixture was stirred at 70° C. overnight. Aftercompletion of the reaction (monitored by TLC), the mixture was cooled toRT, diluted with water (100 mL) and the aqueous layer was extracted withEtOAc (2×100 mL). The combined organic layer was washed with water (100mL), brine (100 mL), dried over anhydrous Na₂SO₄ and concentrated undervacuum. The resulting crude material was triturated with EtOAc to affordthe title compound. Yield: 66% (25 g, off white solid). ¹H NMR (400 MHz,CDCl₃): δ 7.56 (d J=8.0 Hz 1H), 7.49 (s, 1H), 7.31-7.25 (m, 15 H), 7.10(dd, J=8.2, 1.2 Hz, 1H), 4.93 (s, 1H), 3.19 (dd, J=9.8, 6.8 Hz, 1H),3.07 (d, J=7.6 Hz, 1H), 1.22 (d, J=6.4 Hz, 3H).

Step 3: (S)-2-(2, 5-dibromophenoxy) propan-1-ol

To a stirred solution of (S)-((2-(2,5-dibromophenoxy)propoxy)methanetriyl)tribenzene (25 g, 45.28 mol) indry DCM (250 mL), 10% TFA in DCM (100 mL) was added slowly at −20° C.and the reaction mixture was stirred for 2 h. Completion of the reactionwas monitored by TLC, then the reaction mixture was quenched with sat.Na₂CO₃ at 0° C. and the aqueous layer was extracted with DCM (2×150 mL).The combined organic layer was washed with brine (40 mL), dried overanhydrous Na₂SO₄ and concentrated under vacuum. The resulting crudematerial was purified by recrystallization using methanol to afford thetitle compound. Yield: 57% (8.0 g, pale brown gummy oil). ¹H NMR (400MHz, CDCl₃): δ 7.41 (d, J=8.3 Hz, 1H), 7.12 (d, J=2.0 Hz, 1H), 7.02 (dd,J=6.4, 2.1 Hz, 1H), 4.50 (t, J=4.4 Hz, 1H) 3.78 (t, J=4.1 Hz, 2H), 1.36(d, J=6.2 Hz, 3H). HPLC: (Method A), Rt. 4.4 min, 97.1% (Max). ChiralSFC: (Method D) Rt. 3.3 min, 99.1% (Max).

Step 4: (S)-1, 4-dibromo-2-((1-bromopropan-2-yl)oxy)benzene

To a stirred solution of TPP (14.21 g, 0.06 mol) in DCM (50 ml), CBr₄(19.8 g, 0.06 mmol) was added slowly portion wise at 0° C. over 15 min,then (S)-2-(2, 5-dibromophenoxy) propan-1-ol (5.6 g, 0.02 mol) in DCM(20 mL) was added to it and the reaction mixture was stirred for 2 h atRT. Completion of the reaction was monitored by TLC, then the reactionmixture was evaporated under vacuum. The resulting crude material waspurified by flash chromatography (Biotage Isolera, eluent: 10% EtOAc inhexane) to afford the title compound. Yield: 83% (5.1 g, pale browngummy solid). ¹H NMR: (400 MHz, DMSO-d₆): δ 7.53 (d, J=8.4 Hz, 1H), 7.43(d, J=1.6 Hz, 1H), 7.11 (dd, J=8.4, 2.0 Hz, 1H), 4.90-4.88 (m, 1H), 3.77(dd, J=11.0, 3.6 Hz, 1H), 3.67 (dd, J=11.2, 5.2, Hz, 1H), 1.34 (d, J=6.0Hz, 3H).

Step 5: (S)-2-methyl-2, 3-dihydrobenzofuran-6-carbaldehyde

To a stirred solution of (S)-1,4-dibromo-2-((1-bromopropan-2-yl)oxy)benzene (5.1 g, 0.01 mol) in dryTHF (51 mL) under nitrogen atmosphere, n-Butyl lithium (9.42 mL, 0.02mol, 1.6 M in hexane) was added slowly over 10 min at −78° C. After 1 hat the same temperature second lot of n-Butyl lithium (9.42 mL, 0.02mol, 1.6 M in hexane) was added slowly over 10 min and stirring wascontinued for another 1 h. Then DMF (2.15 mL, 27.4 mmol) was addedslowly maintaining at −78° C. for 45 min and completion of the reactionwas monitored by TLC. The reaction mixture was then warmed to 10° C.,quenched with sat. NH₄Cl solution (20 mL) and the aqueous layer wasextracted with EtOAc (2×25 mL). The combined organic layer was washedwith water (10 mL), brine solution (5 mL), dried over anhydrous Na₂SO₄and evaporated under vacuum. The resulting crude material was purifiedby flash chromatography (Biotage Isolera, eluent: 8% EtOAc in hexane) toafford the title compound. Yield: 72% (1.6 g, brown gummy oil). ¹H NMR(400 MHz, CDCl₃): δ 9.93 (s, 1H), 7.39 (d, J=7.2 Hz, 1H), 7.33 (d, J=2.4Hz, 1H), 7.29 (dd, J=7.8, 1.6, Hz, 1H), 5.05-5.01 (m, 1H), 3.40 (dd,J=16.4, 8.8 Hz, 1H), 2.90 (dd, J=16.6, 7.6 Hz, 1H), 1.51 (d, J=6.2 Hz,3H). LCMS: (Method A) 163.1 (M+H), Rt. 2.5 min, 69.9% (Max).

Step 6: 1-((S)-2-methyl-2, 3-dihydrobenzofuran-6-yl)ethan-1-ol

To a stirred solution of (S)-2-methyl-2,3-dihydrobenzofuran-6-carbaldehyde (1.6 g, 9.80 mmol) in dry THF (16 mL)under nitrogen atmosphere, methyl magnesium chloride solution (4.9 mL,0.02 mol, 3 M in THF) was added dropwise over 10 min at 0° C. andstirred for 2 h at the same temperature. After completion of thereaction (monitored by TLC), the mixture was quenched by sat. NH₄Clsolution (10 mL) and the aqueous layer was extracted with EtOAc (2×15mL). The combined organic layer was washed with water (5 mL), brinesolution (2 mL), dried over anhydrous Na₂SO₄ and evaporated at 45° C.under vacuum. The resulting crude material was purified by flashchromatography (Biotage Isolera, eluent: 18% EtOAc in pet ether) toafford the title compound. Yield: 69% (1.22 g, pale yellow liquid). ¹HNMR (400 MHz, CDCl₃): δ 7.14 (d, J=7.6 Hz, 1H), 6.86 (dd, J=7.6, 1.8,Hz, 1H), 6.81 (s, 1H), 4.98-4.93 (m, 1H), 4.84 (q, J=6.4 Hz, 1H), 3.32(dd, J=15.2, 8.8 Hz, 1H), 2.82 (dd, J=15.6, 7.6 Hz, 1H), 1.56 (d, J=6.2Hz, 3H), 1.47 (d, J=6.8 Hz, 3H). LCMS: (Method A) 161.1 (M−H₂O+H), Rt2.2 min, 97.3% (Max).

Step 7: (2S)-6-(1-chloroethyl)-2-methyl-2, 3-dihydrobenzofuran

To a stirred solution of 1-((S)-2-methyl-2,3-dihydrobenzofuran-6-yl)ethan-1-ol (1.2 g, 6.7 mmol) in DCM (12 mL),SOCl₂ (1.5 mL, 20.1 mmol) was added at 0° C. and the reaction mixturewas stirred at RT for 1 h. After completion of the reaction, thereaction mixture was concentrated under vacuum and the resulting crudematerial was co-distilled with dry DCM (3×5 mL) to afford the titlecompound. Yield: 98% (crude) (1.2 g, brown gummy oil).

Intermediate 6: 6-(1-chloroethyl)-2,2-dimethyl-2,3-dihydrobenzofuran

Step 1: 1-bromo-3-((2-methylallyl) oxy)benzene

To a stirred solution of 3-bromophenol (Oakwood products, 10.0 g, 28.90mmol) in dry acetone (60 mL), K₂CO₃ (8 g, 86.7 mmol) was added at RT andstirred for 10 min. Then 2-methyl-3-bromopropene (3.2 mL, 31.7 mmol) wasadded and the reaction mixture was refluxed for 6 h. Completion of thereaction was monitored by TLC, the reaction mixture was then filteredand the filtrate part was concentrated under vacuum. The resulting crudematerial was used in the next step without any further purification.Yield: 84% (11.0 g, brown liquid). ¹H NMR (400 MHz, CDCl₃): 7.28 (s,1H), 7.17-7.01 (m, 2H), 6.89-6.86 (m, 1H), 5.10 (s, 1H), 5.02 (s, 1H),4.44 (s, 2H), 1.85 (s, 3H).

Step 2: 5-bromo-2-(2-methylallyl) phenol and 3-bromo-2-(2-methylallyl)phenol

1-Bromo-3-((2-methylallyl)oxy) benzene (11.0 g, 48.4 mmol) was added inpolyethylene glycol (50 mL) at RT and the reaction mixture was stirredat 250° C. for 1 h under microwave irradiation. After completion of thereaction (monitored by TLC), water (100 mL) was added to the resultingmixture and the aqueous layer was extracted with EtOAc (2×100 mL). Thecombined organic layer was dried over Na₂SO₄ and concentrated undervacuum. The resulting crude material was purified by flashchromatography (Biotage Isolera, eluent: 30-50% EtOAc in pet ether) toafford the title compound. The mixture of regioisomers (1.4:1) was usedas such for the next step. Yield: 91% (10 g, brown liquid). ¹H NMR (400MHz, CDCl₃): δ 7.28 (s, 1H), 7.21-6.90 (m, 2H), 6.96-6.80 (m, 2H), 3.34(s, 2H), 1.82 (s, 3H). LCMS: (Method B) 225.0 (M−H), Rt1: 6.4 min,52.3%, Rt 2: 6.6 min, 36.3% (Max).

Step 3: 6-bromo-2, 2-dimethyl-2, 3-dihydrobenzofuran and 4-bromo-2,2-dimethyl-2, 3-dihydrobenzofuran

A stirred solution of 5-bromo-2-(2-methylallyl)phenol and3-bromo-2-(2-methylallyl)phenol regioisomer mixture (10 g, 44.0 mmol) informic acid (30 mL) was refluxed for 10 h. Completion of the reactionwas monitored by TLC and the reaction mixture was concentratedcompletely under vacuum. The resulting crude material was purified byflash chromatography (Biotage Isolera, eluent: 15% EtOAc in pet ether)to afford the title compound. The mixture of regioisomer was forwardedto the next step as such. Yield: 80% (8 g, dark brown liquid). ¹H NMR(400 MHz, CDCl₃): δ 6.98 (t, J=2.0 Hz, 1H), 6.96 (s, 1H), 6.66 (dd,J=6.8, 2.4 Hz, 1H), 3.03 (d, J=1.2 Hz, 1H), 2.96 (s, 1H), 1.51 (d, J=2.0Hz, 3H), 1.48 (d, J=2.0 Hz, 3H).

Step 4: 1-(2,2-dimethyl-2, 3-dihydrobenzofuran-6-yl)ethan-1-one (IsomerA) and 1-(2,2-dimethyl-2,3-dihydrobenzofuran-4-yl)ethan-1-one (Isomer B)

To a degassed solution of 6-bromo-2, 2-dimethyl-2, 3-dihydrobenzofuranand 3-bromo-2, 2-dimethyl-2, 3-dihydrobenzofuran regioisomer mixture(7.6 g, 33.5 mmol) in dry toluene (100 mL), 1-ethoxy vinyl tributyl tin(14 ml, 40.15 mmol) and Pd(PPh₃)₂Cl₂ (940 mg, 1.2 mmol) were added andthe resulting mixture was heated at 90° C. overnight. Completion of thereaction was monitored by TLC, then an aqueous solution of HCl (6N, 50mL) was added and the mixture was stirred at 40° C. for 1 h. Thereaction mixture was basified (pH-8) by using solid NaHCO₃, filteredthrough celite and washed with EtOAc (100 mL). The organic layer wasseparated, washed with brine solution (100 mL), dried over anhydrousNa₂SO₄ and evaporated under vacuum. The resulting crude material waspurified by flash chromatgraphy (Biotage Isolera, eluent: 55% EtOAc inpet ether) to afford the isomer A and isomer B.

Isomer A analysis: Yield: 30% (2.2 g, pale yellow liquid). ¹H NMR (400MHz, CDCl₃): δ 7.45 (dd, J=7.6, 1.2 Hz, 1H), 7.29 (d, J=1.2 Hz, 1H),7.21 (d, J=7.6 Hz, 1H), 3.05 (s, 2H), 2.56 (s, 3H), 1.50 (s, 6H). LCMS:(Method A) 191.0 (M+H), Rt 4.0 min, 98.4% (Max).

Isomer B analysis: Yield: 15% (500 mg, pale yellow liquid). ¹H NMR (400MHz, CDCl₃): δ 7.37 (d, J=8.0 Hz, 1H), 7.23 (t, J=8.0 Hz, 1H), 6.93 (d,J=8.0 Hz, 1H), 3.36 (s, 2H), 2.59 (s, 3H), 1.48 (s, 6H). LCMS: (MethodA) 191.0 (M+H), Rt. 4.2 min, 99.2% (Max).

Step 5: 1-(2, 2-dimethyl-2, 3-dihydrobenzofuran-6-yl)ethan-1-ol

To a stirred solution of 1-(2, 2-dimethyl-2,3-dihydrobenzofuran-6-yl)ethan-1-one (Isomer A, 2.1 g, 11.0 mmol) inmethanol (11 mL) at 0° C., NaBH₄ (838 mg, 22.0 mmol) was added and thereaction mixture was stirred at RT for 60 min. After completion of thereaction (monitored by TLC), the mixture was quenched with ice-coldwater (5 mL) and extracted with DCM (2×30 mL). The combined organiclayer was washed with brine (20 mL), dried over Na₂SO₄ and concentratedunder vacuum to afford the title compound. Yield: 76% (crude) (1.6 g,brown liquid). ¹H NMR (400 MHz, CDCl₃): δ 7.28 (s, 1H), 7.12 (d, J=7.6Hz, 1H), 6.85 (d, J=1.2 Hz, 1H), 4.88-4.83 (m, 1H), 3.01 (s 2H),1.50-1.48 (m, 9H). LCMS: (Method A) 175.0 (M+H), Rt. 3.5 min, 96.9%(Max).

Step 6: 6-(1-chloroethyl)-2, 2-dimethyl-2, 3-dihydrobenzofuran

To a stirred solution of 1-(2, 2-dimethyl-2,3-dihydrobenzofuran-6-yl)ethan-1-ol (1.6 g, 8.32 mmol) in DCM (10 mL),SOCl₂ (2.0 mL, 24.9 mmol) was added at 0° C. and the mixture was stirredat RT for 2 hr. After completion of the reaction (monitored by TLC), themixture was then concentrated under vacuum to afford the title compoundwhich was used in the next step without any further purification. Yield:91% (1.75 g, pale brown gummy solid).

Intermediate 7:1-(1-(2-methyl-2,3-dihydrobenzofuran-6-yl)ethyl)piperazinedihydrochloride

Step 1: tert-butyl4-(1-(2-methyl-2,3-dihydrobenzofuran-6-yl)ethyl)piperazine-1-carboxylate

To a stirred solution of 1-Boc-piperazine (658 mg, 11.7 mmol) in DMF (3mL), intermediate 1 (580 mg, 2.9 mmol) and TEA (1.60 mL, 11.7 mmol) wereadded and the reaction mixture was heated at 70° C. overnight.Completion of the reaction was monitored by TLC, then the reactionmixture was evaporated under vacuum. To the resulting mixture, water (5mL) was added and the aqueous layer was extracted with EtOAc (2×15 mL).The combined organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated under vacuum. The resulting crude material was purified byflash chromatography (Biotage Isolera, eluent: 35% EtOAc in pet ether)to afford the title compound. Yield: 31% (250 mg, pale brown gum). ¹HNMR (400 MHz, CDCl₃): δ 7.06 (d, J=7.6 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H),6.70 (s, 1H), 4.96-4.92 (m, 1H), 3.47-3.27 (m, 5H), 2.86-2.82 (m, 1H),2.45-2.42 (m, 5H), 1.47-1.42 (m, 12H), 1.36 (d, J=6.4 Hz, 3H). LCMS:(Method A) 347.3 (M+H), Rt. 3.7 min, 63.4% (Max).

Step 2: 1-(1-(2-methyl-2, 3-dihydrobenzofuran-6-yl)ethyl)piperazinedihydrochloride

To a stirred solution of tert-butyl4-(1-(2-methyl-2,3-dihydrobenzofuran-6-yl)ethyl)piperazine-1-carboxylate(250 mg, 0.08 mmol) in dry 1, 4 dioxane (5 mL), HCl solution in dioxane(10 mL, 4M) was added at 0° C. dropwise and the reaction mixture wasstirred at RT for 2 h. After completion of the reaction (monitored byTLC), the mixture was concentrated under vacuum to afford the tittlecompound. Yield: 93% (600 mg, off white solid). ¹H NMR (400 MHz,DMSO-d₆): 9.79-9.61 (m, 2H), 7.26 (d, J=7.6 Hz, 1H), 7.09-7.03 (m, 2H),4.97-4.51 (m, 1H), 3.51 (q, J=6.6 Hz, 1H), 3.83-3.31 (m, 8H), 3.16-3.13(m, 2H), 1.67 (d, J=6.6 Hz, 3H), 1.52 (d, J=6.4 Hz, 3H).

Intermediate 8:N-((2-chloropyrimidin-5-yl)(methyl)(oxo)-λ⁶-sulfanylidene)-2,2,2-trifluoroacetamide

Step 1: 2-chloro-5-(methylthio)pyrimidine

To a stirred solution of 5-bromo-2-chloropyrimidine (5 g, 25.8 mmol) and1, 2-dimethyldisulfane (2.92 g, 31.02 mmol) in THF (15 mL), n-BuLi (16.0mL, 25.8 mmol, 1.6 M in hexane) was added at -78° C. and stirred for 1 hunder the same temperature. After completion of the reaction (monitoredby TLC), the reaction was then quenched with the addition of sat.NH₄Cl(15 mL) and the aqueous layer was extracted with EtOAc (50 mL). Theorganic layer was washed with water (10 mL), brine (10 mL) and driedover anhydrous Na₂SO₄. The resulting crude material was purified byflash chromatography (silica gel: 60-120 mesh, eluent: 15% EtOAc in petether) to afford the title compound. Yield: 13% (0.6 g, white solid). ¹HNMR (400 MHz, CDCl₃): δ 8.50 (s, 2H), 2.56 (s, 3H). LCMS: (Method A)161.1 (M+H), Rt. 2.1 min, 95.2% (Max). HPLC: (Method A) Rt. 2.4 min,98.5% (Max).

Step 2: 2-chloro-5-(methylsulfinyl)pyrimidine

To a stirred solution of 2-chloro-5-(methylthio)pyrimidine (0.6 g, 2.49mmol) in DCM (2 mL, 10 V), m-CPBA (0.644 g, 3.23 mmol) was added portionwise at 0° C. for 30 min. Completion of the reaction was monitored byTLC, the reaction mixture was then quenched with 10% NaHCO₃ solution andextracted with DCM (2×100 mL). The combined organic layer was washedwith brine (30 mL), dried over anhydrous Na₂SO₄ and concentrated undervacuum. The resulting crude material was purified by flashchromatography (Biotage Isolera, eluent: 10-12% EtOAc in pet ether) toafford the title compound. Yield: 33% (330 mg, off white solid). ¹H NMR(400 MHz, DMSO-d₆): δ 8.88 (s, 2H), 2.92 (s, 3H). LCMS: (Method A) 177.1(M+H), Rt. 0.8 min, 99.1% (Max). HPLC: (Method A) Rt. 1.9 min, 99.6%(Max).

Step 3: N-((2-chloropyrimidin-5-yl)(methyl)(oxo)-λ⁶-sulfanylidene)-2,2,2-trifluoroacetamide

To a stirred solution of 2-chloro-5-(methylsulfinyl)pyrimidine (0.9 g,5.09 mmol) in DCM (18.0 mL, 20 V), trifluoroacetamide (1.15 g, 10.19mmol), MgO (0.8 g, 20.38 mmol), Rh₂(OAc)₄ (0.12 g, 0.25 mmol) andPhI(OAC)₂ (2.46 g, 7.64 mmol) were added and the reaction mixture wasstirred at RT overnight. Completion of the reaction was monitored byTLC, the reaction mixture was then filtered through celite and thefiltrate was concentrated under vacuum. The resulting crude material waspurified by flash chromatography (Biotage Isolera, eluent: 16-18% EtOAcin pet ether) to afford the title compound. Yield: 74% (1.1 g, whitesolid). LCMS: (Method A) 288.0 (M+H), Rt. 3.8 min, 71.1% (Max).

Intermediate 9:1-(1-((R)-2-methyl-2,3-dihydrobenzofuran-6-yl)ethyl)piperazinedihydrochloride

Step 1: tert-butyl4-(1-((R)-2-methyl-2,3-dihydrobenzofuran-6-yl)ethyl)piperazine-1-carboxylate

To a stirred solution of 1-Boc-piperazine (3.18 g, 17.08 mmol) in DMF(5.6 mL), intermediate 4 (2.8 g, 14.23 mmol) followed by TEA (8.00 mL,56.94 mmol) were added slowly at RT and the reaction mixture was heatedat 80° C. overnight. Completion of the reaction was monitored by TLC,then the reaction mixture was evaporated under vacuum. To the resultingmixture, water (20 mL) was added and the aqueous layer was extractedwith EtOAc (2×25 mL). The combined organic layer was washed with brinesolution (10 mL), dried over anhydrous Na₂SO₄, filtered and concentratedunder vacuum. The resulting crude material was purified by flashchromatography (Biotage Isolera, eluent: 12% EtOAc in pet ether) toafford the title compound. Yield: 71% (3.45 g, pale brown gummy liquid).¹H NMR (400 MHz, CDCl₃): δ 7.08 (d, J=7.6 Hz, 1H), 6.75 (t, J=7.6 Hz,2H), 4.96-4.92 (m, 1H), 3.40-3.25 (m, 6H), 2.80 (dd, J=15.4, 8.4 Hz,1H), 2.41-2.37 (m, 4H), 1.49-1.44 (m, 12H), 1.35 (d, J=6.4 Hz, 3H).LCMS: (Method A) 347.2 (M+H), Rt 2.37 min, 81.0% (Max).

Step 2: 1-(1-((R)-2-methyl-2,3-dihydrobenzofuran-6-yl)ethyl)piperazinedihydrochloride

To a stirred solution of tert-butyl4-(1-((R)-2-methyl-2,3-dihydrobenzofuran-6-yl)ethyl)piperazine-1-carboxylate(3.4 g, 9.82 mmol) in dry 1, 4-dioxane (10 mL), HCl solution in dioxane(17 mL, 4M) was added dropwise at 0° C. and the reaction mixture wasstirred at RT for 2 h. After completion of the reaction (monitored byTLC), the mixture was concentrated under vacuum and the resulting crudematerial was triturated with EtOAc to afford the tittle compound. Yield:94% (2.9 g, pale brown solid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.27 (d,J=7.6 Hz, 1H), 7.08 (q, J=4.4 Hz, 2H), 4.97-4.91 (m, 1H), 4.52 (s, 1H),3.86-3.84 (m, 1H), 3.65-3.60 (m, 4H), 3.57 (m, 1H), 3.49-3.30 (m, 4H),2.81-2.77 (m, 1H) 1.70 (d, J=6.4 Hz, 3H), 1.40 (d, J=6.4 Hz, 3H). LCMS:(Method A) 247.2 (M+H), Rt 1.7 min, 81.7% (Max).

Intermediate 10: 1-(1-(2,2-dimethyl-2,3-dihydrobenzofuran-6-yl)ethyl)piperazine dihydrochloride

Step 1: tert-butyl 4-(1-(2, 2-dimethyl-2,3-dihydrobenzofuran-6-yl)ethyl)piperazine-1-carboxylate

To a stirred solution of 1-boc-piperazine (960 mg, 22.19 mmol) in DMF (3mL), intermediate 6 (900 mg, 4.21 mmol) was added and the reactionmixture was heated at 70° C. overnight. Completion of the reaction wasmonitored by TLC, then the reaction mixture was evaporated under vacuum.To the resulting mixture, water (5 mL) was added and the aqueous layerwas extracted with EtOAc (2×15 mL). The combined organic layer was driedover anhydrous Na₂SO₄, filtered and concentrated under vacuum. Theresulting crude material was purified by flash chromatography (BiotageIsolera, eluent: 35% EtOAc in pet ether) to afford the title compound.Yield: 46% (700 mg, pale brown gummy solid). ¹H NMR (400 MHz, CDCl₃): δ7.06 (d, J=7.6 Hz, 1H), 6.75 (q, J=8.0 Hz, 1H), 6.70 (s, 1H), 3.47-3.32(m, 4H), 2.99 (s, 2H), 2.86-2.85 (m, 2H), 2.45-2.44 (m, 2H), 1.47-1.35(m, 15H). 1.36 (d, J=6.4 Hz, 3H). LCMS: (Method A) 361.0 (M+H), Rt. 3.7min, 63.4% (Max).

Step 2: 1-(1-(2,2-dimethyl-2, 3-dihydrobenzofuran-6-yl)ethyl)piperazinedihydrochloride

To a stirred solution of tert-butyl 4-(1-(2, 2-dimethyl-2,3-dihydrobenzofuran-6-yl)ethyl)piperazine-1-carboxylate (700 mg, 1.94mmol) in dry 1, 4 dioxane (5 mL), HCl solution in dioxane (4M, 10 mL)was added at 0° C. and stirred at RT for 2 h. Completion of the reactionwas monitored by TLC, the reaction mixture was then concentrated underreduced pressure to afford the tittle compound. Yield: 93% (600 mg, offwhite solid). ¹H NMR (400 MHz, CDCl₃): 12.3 (s, 1H), 9.64 (s, 2H), 7.26(d, J=6.8 Hz, 1H), 7.05-7.04 (m, 2H), 4.50 (bs, 1H), 3.80-3.10 (m, 1H),3.40-3.10 (m, 9H), 1.67 (s, 3H), 1.42-1.41 (m, 6H). LCMS: (Method A)261.2 (M+H), Rt. 1.8 min, 82.2% (Max).

Example 1:N-(5-(4-(1-(2-methyl-2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

To a stirred solution of intermediate 1 (0.200 g, 1.01 mmol) in DMF (2.5mL), TEA (0.5 mL, 4.1 mmol) and intermediate 2 (0.254 g, 1.1 mmol) wereadded at RT and the reaction mixture was heated at 70° C. overnight.Completion of reaction was monitored by TLC, then the reaction mixturewas concentrated under vacuum. The resulting crude material was purifiedby flash chromatography (Biotage Isolera, eluent: 2-4% methanol in DCM)to afford the title compound. Yield: 10% (38.8 mg, pale brown solid). ¹HNMR (400 MHz, CDCl₃): δ 7.12 (d, J=7.6 Hz, 1H), 6.75 (d, J=7.2 Hz, 1H),6.68 (s, 1H), 4.89 (d, J=5.6 Hz, 1H), 3.34-3.31 (m, 4H), 3.24 (s, 1H),2.78-2.76 (m, 2H), 2.51-2.43 (m, 4H), 2.10 (s, 3H), 1.39 (d, J=4.0 Hz,3H), 1.28 (d, J=6.0 Hz, 3H). LCMS: (Method A) 388.3 (M+H), Rt. 2.6 min,97.9% (Max). HPLC: (Method A) Rt. 2.6 min, 95.9% (Max).

Example 2:2-(4-(1-(2-methyl-2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one

To a stirred solution of1-(2-methyl-2,3-dihydrobenzofuran-5-yl)ethan-1-ol (200 mg, 1.0 mmol,synthesis described in intermediate 1, steps 1 to 4) in DCM (10 mL),thionyl chloride (1 ml) was added dropwise at 0° C. and the reactionmixture was stirred at RT for 1 h. After completion of the reaction(monitored by TLC), the reaction mixture was evaporated under vacuum andco-distilled with DCM (2×10 mL). The resulting mixture was dissolved inDCM (10 ml) and was added to a mixture of intermediate 3 (288 g, 1.28mmol) and TEA (54 mg, 5.3 mmol) in DCM (10 mL) drop wise at RT and thereaction mixture was stirred at RT overnight. Completion of the reactionwas monitored by TLC, then the reaction mixture was evaporated undervacuum. The resulting crude material was purified by flashchromatography (Biotage Isolera, eluent: 75-80% EtOAc in pet ether) toafford the title compound. Yield: 25% (20 mg, pale brown solid). ¹H NMR(400 MHz, DMSO-d₆): δ 8.58 (s, 1H), 7.69 (s, 1H), 7.11 (d, J=7.6 Hz,1H), 6.75 (d, J=7.2 Hz, 1H), 6.68 (s, 1H), 4.89-4.87 (m, 1H), 3.80-3.79(m, 4H), 3.38-3.24 (m, 5H), 2.80-2.67 (m, 4H), 2.46-2.43 (m, 1H),2.37-2.33 (m, 1H), 1.39-1.37 (m, 3H), 1.28 (d, J=6.8 Hz, 3H). LCMS:(Method A) 394.5 (M+H), Rt. 2.6 min, 97.8% (Max). HPLC: (Method A) Rt.2.6 min, 97.9% (Max).

Example 3:Imino(methyl)(2-(4-(1-(2-methyl-2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)-λ⁶-sulfanone

Step 1:Imino(methyl)(2-(4-(1-(2-methyl-2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)-λ⁶-sulfanone

To a stirred solution of intermediate 7 (300 mg, 0.90 mmol) in DMF (2.5mL), TEA (0.7 mL, 4.80 mmol) and intermediate 8 (300 mg, 1.2 mmol) wereadded at RT and stirred overnight. Completion of the reaction wasmonitored by TLC, then the reaction mixture was evaporated at 50° C.under vacuum. To the resulting mixture, water (5 mL) was added and theaqueous layer was extracted with EtOAc (2×50 mL). The combined organiclayer was dried over Na₂SO₄ and concentrated under vacuum. The resultingcrude material was purified by flash chromatography (silica gel: 230-400mesh, eluent: 50% EtOAc in pet-ether) to obtain2,2,2-trifluoro-N-(methyl(2-(4-(1-(2-methyl-2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)(oxo)-λ⁶-sulfanylidene)acetamide.Yield: 30% (150 mg, off white solid).

To this intermediate methanol (7 mL, 20 V) and K₂CO₃ (414 mg, 4.53 mmol)were added, and the resulting mixture was stirred at RT for 20 min.After 20 min, the reaction mixture was filtered through celite andconcentrated under vacuum. To the resulting mixture, water (20 mL) wasadded and the aqueous layer was extracted with DCM (2×100 mL). Thecombined organic layer was dried over anhydrous Na₂SO₄ and concentratedunder vacuum. The resulting crude material was purified by flashchromatography (Biotage Isolera, gradient: 1-2% methanol in DCM) toafford the title compound. Yield: 20% (75 mg, off white solid). ¹H NMR(400 MHz, DMSO-d₆): δ 8.66 (s, 2H), 7.11 (d, J=7.6 Hz, 1H), 6.75 (d,J=7.6 Hz, 1H), 6.68 (s, 1H), 4.89-4.87 (m, 1H), 4.24 (s, 1H), 3.82-3.81(m, 4H), 3.37-3.20 (m, 2H), 3.08 (s, 3H), 2.76-2.71 (m, 1H), 2.47-2.33(m, 4H), 1.38 (q, J=2.4 Hz, 3H), 1.28 (d, J=6.4 Hz, 3H). LCMS: (MethodA) 402.0 (M+H), Rt 2.4 min, 99.0% (Max). HPLC: (Method A) Rt 2.4 min,98.3% (Max).

Example 4:N-(5-(4-(1-(2,2-dimethyl-2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

To a stirred solution of intermediate 2 (356 mg, 1.56 mmol) and TEA (0.8ml mg, 5.6 mmol) in dry DMF (3 mL), intermediate 6 (300 mg, 1.4 mmol)was added and the reaction mixture was heated at 75° C. overnight.Completion of the reaction was monitored by TLC, then the reactionmixture was evaporated at 45° C. under vacuum. To the resulting mixture,water (4 mL) was added and the aqueous layer was extracted with EtOAc(3×20 mL). The combined organic layer was washed with brine solution (10mL), dried over anhydrous Na₂SO₄ and concentrated under vacuum. Theresulting crude material was purified by flash chromatography (BiotageIsolera, eluent: 4-5% methanol in DCM) to afford the title compound.Yield: 7% (39.4 mg, off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 12.00(s, 1H), 7.09 (d, J=7.6 Hz, 1H), 6.73 (d, J=7.6 Hz, 1H), 6.63 (s, 1H),3.37-3.33 (m, 4H), 2.96 (s, 2H), 2.50-2.35 (m, 4H), 2.09 (s, 3H), 1.40(s, 3H), 1.39 (s, 3H), 1.27 (d, J=6.4 Hz, 3H). LCMS: (Method A) 402.0(M+H), Rt. 2.8 min, 94.7% (Max). HPLC: (Method A) Rt 2.7 min, 96.3%(Max).

Example 5:(2-(4-(1-(2,2-dimethyl-2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)(imino)(methyl)-λ⁶-sulfanone

To a stirred solution of Intermediate 10 (400 mg, 1.20 mmol) in DMF (2.5mL), TEA (0.7 mL, 4.80 mmol) and intermediate 8 (344 mg, 1.20 mmol,synthesis described in example 3, steps 1 to 5) were added at RT and thereaction mixture was stirred overnight. Completion of the reaction wasmonitored by TLC, then the reaction mixture was evaporated at 50° C.under reduced pressure. To the resulting mixture, water (2 mL) was addedand the aqueous layer was extracted with EtOAc (2×50 mL). The combinedorganic layer was dried over anhydrous Na₂SO₄ and concentrated undervacuum. The resulting crude material was purified by flashchromatography (silica gel: 230-400 mesh, eluent: 50% EtOAc inpet-ether) to obtainN-((2-(4-(1-(2,2-dimethyl-2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)(methyl)(oxo)-λ⁶-sulfanylidene)-2,2,2-trifluoroacetamide.Yield: 23% (180 mg, off white solid). To this intermediate methanol (7mL, 20 V) and K₂CO₃ (414 mg, 4.53 mmol) were added and stirred for 20min. After 20 min, the reaction mixture was filtered through celite andconcentrated under vacuum. To the resulting mixture, water (20 mL) wasadded and the aqueous layer was extracted with DCM (2×100 mL). Thecombined organic layer was dried over anhydrous Na₂SO₄ and concentratedunder vacuum. The resulting crude material was purified by flashchromatography (Biotage Isolera, gradient: 1-2% methanol in DCM) toafford the title compound. Yield: 18% (83.6 mg, off white solid). ¹H NMR(400 MHz, DMSO-d₆): δ 8.66 (s, 2H), 7.10 (d, J=7.6 Hz, 1H), 6.74 (d,J=7.6 Hz, 1H), 6.65 (s, 1H), 4.24 (s, 1H), 3.82 (s, 4H), 3.38 (t, J=6.8Hz, 1H), 3.08 (s, 3H), 2.96 (s, 2H), 2.39-2.33 (m, 4H), 1.41-1.39 (m,6H), 1.29 (d, J=6.8 Hz, 3H). LCMS: (Method A) 416.0 (M+H), Rt. 2.6 min,99.6% (Max). HPLC: (Method A) Rt 2.5 min, 99.8% (Max).

Example 6:2-(4-(1-(2,2-dimethyl-2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one

To a stirred solution of intermediate 6 (300 mg, 1.4 mmol) in dry DMF (3mL), TEA (0.8 mL, 5.6 mmol) and intermediate 3 (330 mg, 1.7 mmol) wereadded and the reaction mixture was heated at 75° C. overnight.Completion of the reaction was monitored by TLC, then the reactionmixture was evaporated at 45° C. under vacuum. To the resulting mixture,water (4 mL) was added and the aqueous layer was extracted with EtOAc(3×20 mL). The combined organic layer was washed with brine solution (10mL), dried over anhydrous Na₂SO₄ and concentrated under vacuum. Theresulting crude material was purified by flash chromatography (BiotageIsolera, eluent: 4-5% methanol in DCM) to afford the title compound.Yield: 22% (116.19 mg, off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ8.58 (s, 1H), 7.70 (s, 1H), 7.10 (d, J=7.6 Hz, 1H), 6.74 (d, J=7.2 Hz,1H), 6.65 (s, 1H), 3.80-3.79 (s, 4H), 3.37-3.36 (m, 3H), 2.96 (s, 2H),2.80-2.77 (t, J=6.8 Hz, 2H), 2.37-2.34 (m, 4H), 1.40 (d, J=2.8 Hz, 6H),1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 408.0 (M+H), Rt. 2.8 min, 98.5%(Max). HPLC: (Method A) Rt 2.7 min, 98.9% (Max).

Example 7:1-(1-(2-methyl-2,3-dihydrobenzofuran-6-yl)ethyl)-4-(4-(methylsulfonyl)phenyl)piperazine

Step 1: tert-butyl 4-(4-(methylsulfonyl)phenyl)piperazine-1-carboxylate

To a stirred solution of 1-fluoro-4-(methylsulfonyl)benzene (0.3 g, 1.7mmol) in DMF (3 mL), N-Boc-piperazine (420 mg, 2.24 mmol) and TEA (1.0ml, 6.86 mmol) were added at RT and the reaction mixture was heated at80° C. for 12 h. Completion of the reaction was monitored by TLC, thenthe reaction mixture was concentrated under vacuum. The resulting crudematerial was purified by flash chromatography (Biotage Isolera, eluent:50% EtOAc in pet-ether) to afford the title compound. Yield: 43% (0.7 g,pale yellow colored solid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.00 (d, J=8.8Hz, 2H), 6.82 (d, J=9.2 Hz, 2H), 3.64 (t, J=4.8 Hz, 4H), 3.37 (t, J=4.8Hz, 4H), 3.10 (s, 3H), 1.51 (s, 9H). LCMS: (Method A) 285.2 (M+H-tBu),Rt. 4.1 min, 51.9% (Max).

Step 2: 1-(4-(methylsulfonyl)phenyl)piperazine hydrochloride

To a stirred solution of tert-butyl 4-(4-(methylsulfonyl)phenyl)piperazine-1-carboxylate (0.6 g, 1.7 mmol) in dry 1, 4-dioxane (6mL, 10 V) at 0° C., HCl solution in dioxane (2.2 mL, 4M) was addeddropwise and the reaction mixture was stirred at RT for 10 min.Completion of the reaction was monitored by TLC, then the reactionmixture was concentrated under vacuum. The resulting crude material wastriturated with EtOAc and evaporated under vacuum to afford the titlecompound. Yield: 46% (0.25 g, off white solid). ¹H NMR (400 MHz,DMSO-d₆): δ 7.01 (d, J=16.0 Hz, 2H), 6.82 (d, J=8.0 Hz, 2H), 3.64 (t,J=4.8 Hz, 4H), 3.37 (t, J=4.8 Hz, 4H), 3.10 (s, 3H), 1.8 (s, 1H).

Step 3: 1-(1-(2-methyl-2,3-dihydrobenzofuran-6-yl)ethyl)-4-4-(methylsulfonyl)phenyl)piperazine

To a stirred solution of 1-(4-(methylsulfonyl)phenyl)piperazinehydrochloride (0.22 g, 0.7 mmol) in DMF (2.5 mL), TEA (0.5 mL, 2.8 mmol)and intermediate 1 (0.17 g, 0.84 mmol) were added at RT and the reactionmixture was heated at 70° C. overnight. Completion of the reaction wasmonitored by TLC, then the reaction mixture was concentrated undervacuum. The resulting crude material was purified by flashchromatography (Biotage Isolera, eluent: 1-3% methanol in DCM) and theobtained material was further purified by prep HPLC (method B) to affordthe title compound. Yield: 9% (20 mg, off white solid). ¹H NMR (400 MHz,DMSO-d₆): δ 7.66 (d, J=8.8 Hz, 2H), 7.12 (d, J=7.6 Hz, 1H), 7.04 (d,J=9.2 Hz, 2H), 6.75 (d, J=7.6 Hz, 1H), 6.68 (s, 1H), 4.89 (q, J=1.6 Hz,1H), 3.36-3.24 (m, 6H), 3.08 (s, 3H), 2.75 (q, J=8.0 Hz, 1H), 2.43-2.33(m, 4H), 1.38 (q, J=2.4 Hz, 3H), 1.29 (d, J=6.40 Hz, 3H). LCMS: (MethodA) 401.0 (M+H), Rt. 2.9 min, 99.7% (Max). HPLC: (Method A) Rt. 2.9 min,99.8% (Max).

Example 8:N-(5-(4-(1-(2-methyl-2,3-dihydrofuro[3,2-b]pyridin-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

Step 1: methyl 6-chloro-5-hydroxynicotinate

To a stirred solution of methyl-5-hydroxy nicotinate (10 g, 65.3 mmol,Combi blocks), 40% sodium hypochlorite solution (70 mL, 7V) was added at0° C. for 2 h. Completion of the reaction was monitored by TLC, then 2NHCl solution (50 mL, 5V) was added slowly to the reaction mixture. Theobtained white precipitate was collected by filtration and dried wellunder vacuum to afford the title compound. Yield: 42% (5.1 g, off whitesolid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.38 (s, 1H), 7.77 (s, 1H), 3.89(s, 3H). LCMS: (Method A) 188.2 (M+H), Rt. 2.3 min, 63.1% (Max).

Step 2: methyl 2-methylfuro[3,2-b]pyridine-6-carboxylate

To a degassed solution of methyl 6-chloro-5-hydroxynicotinate (5.1 g,27.4 mmol) in DMF, Pd(dppf)Cl₂ (1.1 g, 1.37 mmol), CuI (0.52 g, 2.74mmol), TEA (7.6 mL, 54.8 mmol) and followed by propargyl trimethylsilane(6.2 mL, 41.1 mmol) were added at RT and the reaction mixture wasstirred at 60° C. overnight. Completion of the reaction was monitored byTLC, then the reaction mixture was filtered through celite and DMF wasconcentrated to dryness under vacuum. The resulting crude material waspurified by flash chromatography (Biotage Isolera, eluent: 15-25% EtOAcin pet ether) to afford the title compound. Yield: 46% (2.4 g, brownsolid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.99 (s, 1H), 8.37 (s, 1H), 6.92(s, 1H), 3.90 (s, 3H), 2.51 (s, 3H). LCMS: (Method A) 192.0 (M+H), Rt.2.1 min, 96.9% (Max).

Step 3: 2-methyl-2,3-dihydrofuro[3,2-b]pyridin-6-yl)methanol

To a stirred solution of methyl2-methylfuro[3,2-b]pyridine-6-carboxylate (2.4 g, 12.5 mmol) in THF, LAH(15.1 mL, 15.07 mmol, 1M in THF) was added at −10° C. dropwise and thereaction mixture was stirred at RT for 1 h. Completion of the reactionwas monitored by TLC, then the reaction mixture was quenched withsaturated NH₄Cl solution (15 mL) and the aqueous layer was extractedwith EtOAc (2×40 mL). The combined organic layer was washed with brinesolution (10 mL), dried over anhydrous Na₂SO₄ and evaporated undervacuum. The resulting crude material was purified by flashchromatography (Biotage Isolera, eluent: 2-4% methanol in DCM) to affordthe title compound. Yield: 55% (1.1 g, brown gummy oil). ¹H NMR (400MHz, DMSO-d₆): δ 8.55 (s, 1H), 8.33 (s, 1H), 5.34 (t, J=7.6 Hz, 1H),5.11-5.00 (m, 1H), 4.61 (d, J=7.2 Hz, 2H), 3.54-3.47 (m, 1H), 3.02-2.96(m, 1H), 1.46 (d, J=6.0 Hz, 3H). LCMS: (Method B) 166.0 (M+H), Rt. 2.5min, 45.1% (Max).

Step 4: 2-methyl-2,3-dihydrofuro[3,2-b]pyridine-6-carbaldehyde

To a stirred solution of2-methyl-2,3-dihydrofuro[3,2-b]pyridin-6-yl)methanol (1.1 g, 6.74 mmol)in DCM, dess-martin periodinane (4.3 g, 10.1 mmol) was added slowly at0° C. and the reaction mixture was stirred at RT for 1 h. Completion ofthe reaction was monitored by TLC, then the reaction mixture wasquenched with saturated NaHCO₃ solution (10 mL) and the aqueous layerwas extracted with DCM (2×30 mL). The combined organic layer was washedwith brine solution (10 mL), dried over anhydrous Na₂SO₄ and evaporatedunder vacuum. The resulting crude material was purified by flashchromatography (Biotage Isolera, eluent: 30% EtOAc in pet ether) toafford the title compound. Yield: 15% (0.15 g, pale yellow solid). ¹HNMR (400 MHz, DMSO-d₆): δ 10.02 (s, 1H), 8.55 (s, 1H), 8.33 (s, 1H),5.11-5.00 (m, 1H), 3.54-3.47 (m, 1H), 3.02-2.96 (m, 1H), 1.46 (d, J=6.0Hz, 3H). LCMS: (Method B) 164.0 (M+H), Rt. 3.9 min, 42.9% (Max).

Step 5: 1-(2-methyl-2,3-dihydrofuro[3,2-b]pyridin-6-yl) ethan-1-ol

To the stirred solution of2-methyl-2,3-dihydrofuro[3,2-b]pyridine-6-carbaldehyde (0.15 g, 0.86mmol) in THF, methyl magnesium chloride (0.5 mL, 1.30 mmol, 3M solutionin THF) was added dropwise at 0° C. and the reaction mixture was stirredat RT for 1 h. Completion of the reaction was monitored by TLC, then thereaction mixture was quenched with saturated NH₄Cl solution (3 mL) andthe aqueous layer was extracted with EtOAc (2×15 mL). The combinedorganic layer was washed with brine solution (5 mL), dried overanhydrous Na₂SO₄ and evaporated under vacuum. The resulting crudematerial was forwarded as such to the next step without any furtherpurification. Yield: 35% (0.05 g, yellow gummy oil). ¹H NMR (400 MHz,DMSO-d₆): δ 8.41 (s, 1H), 7.81 (s, 1H), 5.35 (d, J=4.4 Hz, 1H),5.00-4.89 (m, 1H), 3.54-3.47 (m, 1H), 3.39-3.29 (m, 1H), 3.02-2.96 (m,1H), 1.43 (d, J=8.0 Hz, 3H), 1.31 (d, J=6.4 Hz, 3H). LCMS: (Method A)180.0 (M+H), Rt. 1.2 min, 54.3% (Max).

Step 6: 6-(1-chloroethyl)-2-methyl-2, 3-dihydrofuro[3,2-b]pyridine

To a stirred solution of1-(2-methyl-2,3-dihydrofuro[3,2-b]pyridin-6-yl)ethan-1-ol (0.05 g, 0.27mmol) in DCM, thionyl chloride (0.1 mL, 0.55 mmol) was added dropwise at0° C. and the reaction mixture was stirred at RT for 1 h. Completion ofthe reaction was monitored by TLC, then the reaction mixture wasevaporated under vacuum to afford the title compound. Yield: 97% (0.05g, brown gummy oil). ¹H NMR (400 MHz, DMSO-d₆): δ 8.61 (s, 1H), 8.10 (s,1H), 5.40-5.34 (m, 1H), 5.09-4.97 (m, 1H), 3.54-3.47 (m, 1H), 3.02-2.96(m, 1H), 1.44 (d, J=7.2 Hz, 3H), 1.23 (d, J=7.2 Hz, 3H). LCMS: (MethodA) 198.2 (M+H), Rt. 2.4 min, 45.9% (Max).

Step 7: N-(5-(4-(1-(2-methyl-2,3-dihydrofuro[3,2-b]pyridin-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

To a stirred solution of intermediate 2 (0.17 g, 0.50 mmol) in DMF, TEA(0.18 mL, 1.26 mmol) followed by6-(1-chloroethyl)-2-methyl-2,3-dihydrofuro[3,2-b]pyridine (0.05 g, 0.25mmol) were added at RT and the reaction mixture was stirred at 70° C.overnight. Completion of the reaction was monitored by TLC, then thereaction mixture was evaporated under vacuum. To the resulting mixture,water (2 mL) was added and the aqueous layer was extracted with EtOAc(2×15 mL). The combined organic layer was washed with brine solution (10mL), dried over anhydrous Na₂SO₄ and evaporated under vacuum. Theresulting crude material was purified by flash chromatography (BiotageIsolera, gradient: 0-5% methanol in DCM), then the obtained material wasfurther purified by Prep-HPLC (Method B) to afford the title compound.Yield: 3% (0.002 g, off white solid). ¹H NMR (400 MHz, CDCl₃): δ 7.98(s, 1H), 7.19 (s, 1H), 5.07-5.05 (m, 1H), 3.70-3.65 (m, 4H), 3.49-3.43(m, 1H), 3.30-3.18 (m, 1H), 2.99-2.93 (m, 1H), 2.77-2.74 (m, 4H), 2.34(s, 3H), 1.55 (d, J=3.6 Hz, 3H), 1.27 (d, J=5.2 Hz, 3H). LCMS: (MethodA) 389.0 (M+H), Rt. 1.8 min, 90.2% (Max). HPLC: (Method A) Rt. 1.7 min,90.9% (Max).

Example 9:N-(5-(4-(1-((R)-2-methyl-2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

To a stirred solution intermediate 4 (0.5 g, 0.25 mmol) in DMF (2.5 mL),TEA (1.5 mL, 10.76 mmol) and intermediate 2 (0.64 g, 0.27 mmol) wereadded at RT and the reaction mixture was heated at 70° C. overnight.After completion of the reaction (monitored by TLC), the mixture wasconcentrated under vacuum and the resulting crude material was purifiedby flash chromatography (Biotage Isolera, gradient: 4-8% methanol inDCM) to afford the title compound. Yield: 11% (70 mg, off white solid).¹H NMR (400 MHz, DMSO-d₆): δ 12.02 (s, 1H), 7.11 (d, J=7.2 Hz, 1H), 6.74(d, J=7.2 Hz, 1H), 6.67 (s, 1H), 4.89 (t, J=6.0 Hz, 1H), 3.38-3.24 (m,6H), 2.74 (q, J=7.6 Hz, 1H), 2.43-2.40 (m, 4H), 2.10 (s, 3H), 1.38 (t,J=2.0 Hz, 3H), 1.26 (t, J=6.8 Hz, 3H). LCMS: (Method A) 388.3 (M+H), Rt2.5 min 99.9% (Max). HPLC: (Method A) Rt. 2.6 min, 99.8% (Max).

Example 10:2-(4-(1-((R)-2-methyl-2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one

To a stirred solution of intermediate 3 (0.85 g, 0.27 mmol) in DMF (20mL), TEA (1.5 mL, 10.76 mmol) and intermediate 4 (0.5 g, 0.25 mmol) wereadded at RT and the reaction mixture was heated at 80° C. overnight.Completion of the reaction was monitored by TLC, then the reactionmixture was evaporated under vacuum. To the resulting mixture, water (3mL) was added and the aqueous layer was extracted with EtOAc (2×15 mL).The combined organic layer was washed with brine solution (10 mL), driedover anhydrous Na₂SO₄ and concentrated under vacuum. The resulting crudematerial was purified by flash chromatography (Biotage Isolera,gradient: 4-8% methanol in DCM) to afford the title compound. Yield: 18%(190 mg, off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.58 (d, J=2.8Hz, 1H), 7.70 (s, 1H), 7.11 (d, J=7.6 Hz, 1H), 6.74 (d, J=7.6 Hz, 1H),6.68 (s, 1H), 4.88 (q, J=8.0 Hz, 1H), 3.80 (m, 4H), 3.38-3.23 (m, 4H),2.80-2.71 (m, 3H), 2.51-2.37 (m, 4H), 1.38 (q, J=2.8 Hz, 3H), 1.28 (d,J=6.4 Hz, 3H). LCMS: (Method A) 394.2 (M+H), Rt. 2.5 min, 99.9% (Max).HPLC: (Method A), Rt 2.6 min, 99.8% (Max).

Examples 11 and 12:N-(5-(4-((R)-1-((R)-2-methyl-2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamideandN-(5-(4-((S)-1-((R)-2-methyl-2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

The enantiomers of example 9 was separated by SFC; mobile phase: 20 mMammonia in methanol, column: LUX C3 (Method A), the first eluting peakwas concentrated to afford the example 11 and the second eluting peakwas concentrated to afford the example 12.

Analysis of first eluting fraction (example 11): Yield: 40% (30 mg, offwhite solid). ¹H NMR (400 MHz, DMSO-d₆): δ 12.03 (s, 1H), 7.12 (d, J=7.6Hz, 1H), 6.75 (d, J=7.6 Hz, 1H), 6.68 (s, 1H), 4.89 (q, J=6.4 Hz, 1H),3.40-3.24 (m, 5H), 2.77-2.68 (m, 1H), 2.44-2.39 (m, 4H), 2.10 (s, 3H),1.39 (d, J=6.0 Hz, 3H), 1.27 (t, J=6.4 Hz, 3H). LCMS: (Method A) 388.2(M+H), Rt 2.5 min 99.2% (Max). HPLC: (Method A) Rt. 2.6 min, 99.8%(Max). Chiral SFC: (Method A) Rt. 3.8 min, 100% (Max).

Analysis of second eluting fraction (example 12): Yield: 45% (32 mg, offwhite solid). ¹H NMR (400 MHz, DMSO-d₆): δ 12.03 (s, 1H), 7.12 (d, J=7.2Hz, 1H), 6.75 (d, J=7.6 Hz, 1H), 6.68 (s, 1H), 4.90 (q, J=8.0 Hz, 1H),3.40-3.24 (m, 5H), 2.77-2.68 (m, 1H), 2.42-2.34 (m, 4H), 2.09 (s, 3H),1.38 (d, J=6.0 Hz, 3H), 1.27 (t, J=6.8 Hz, 3H). LCMS: (Method A) 388.3(M+H), Rt. 2.5 min, 98.1% (Max). HPLC: (Method A) Rt. 2.6 min, 99.5%(Max). Chiral SFC: (Method A) Rt. 4.5 min, 99.3% (Max).

Example 13:2-(4-((S)-1-((R)-2-methyl-2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneor2-(4-((R)-1-((R)-2-methyl-2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one

The enantiomers of example 10 was separated by SFC; mobile phase: 20 mMammonia in methanol, column: LUX C3 (Method A), the first elutingfraction was concentrated to afford example 13.

Analysis of first eluting fraction (example 13): Yield: 40% (72 mg, offwhite solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.58 (s, 1H), 7.69 (s, 1H),7.10 (d, J=7.6 Hz, 1H), 6.74 (d, J=7.6 Hz, 1H), 6.68 (s, 1H), 4.88 (q,J=8.4 Hz, 1H), 3.80-3.75 (m, 4H), 3.38-3.17 (m, 4H), 2.80-2.77 (m, 3H),2.43-2.34 (m, 4H), 1.38 (d, J=6.4 Hz, 3H), 1.28 (t, J=6.8 Hz, 3H). LCMS:(Method A) 394.2 (M+H), Rt 2.5 min, 99.9% (Max). HPLC: (Method A), Rt2.6 min, 99.9% (Max). Chiral SFC: (Method A) Rt. 4.0 min, 8.5% (Max).

Example 14:N-(5-(4-(1-((S)-2-methyl-2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

To a stirred solution of intermediate 5 (0.6 g, 0.03 mol) in DMF (6 mL),TEA (2 mL) and intermediate 2 (0.76 g, 0.03 mol) were added at RT andthe reaction mixtue was heated at 70° C. overnight. Completion of thereaction was monitored by TLC, then the reaction mixture wasconcentrated under vacuum. To the resulting mixture, water (2 mL) wasadded and the aqueous layer was extracted with EtOAc (2×25 mL). Thecombined organic layer was washed with brine (10 mL), dried overanhydrous Na₂SO₄ and concentrated under vacuum. The resulting crudematerial was purified by flash chromatography (Biotage Isolera, eluent:4-8% methanol in DCM) to afford the title compound. Yield: 13% (150 mg,off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 12.02 (s, 1H), 7.11 (d,J=7.6 Hz, 1H), 6.75 (d, J=7.2 Hz, 1H), 6.67 (s, 1H), 4.90 (t, J=8.0 Hz,1H), 3.38-3.24 (m, 5H), 2.77-2.71 (m, 1H), 2.51-2.43 (m, 4H), 2.10 (s,3H), 1.38 (q, J=2.4 Hz, 3H), 1.28 (d, J=6.4 Hz, 3H). LCMS: (Method A)388.1 (M+H), Rt 2.0 min, 97.9% (Max). HPLC: (Method A) Rt 2.5 min, 98.6%(Max). Chiral SFC: (Method B), Rt1. 3.8 min, 46.9%, Rt 2. 4.4 min,53.1%.

Example 15:2-(4-(1-((S)-2-methyl-2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one

To a stirred solution of intermediate 3 (1.02 g, 3.35 mmol) in DMF (6mL), intermediate 5 (0.6 g, 3.0 mmol) and TEA (2.0 mL) were added at RTand the reaction mixture was heated at 80° C. overnight. Completion ofthe reaction was monitored by TLC, then the reaction mixture wasevaporated under vacuum. To the resulting mixture, water (10 mL) wasadded and the aqueous layer was extracted with EtOAc (2×25 mL). Thecombined organic layer was washed with brine solution (10 mL), driedover anhydrous Na₂SO₄ and concentrated under vacuum. The resulting crudematerial was purified by flash chromatography (Biotage Isolera,gradient: 4-8% methanol in DCM) to afford the title compound. Yield: 17%(200 mg, off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.58 (s, 1H),7.70 (s, 1H), 7.11 (d, J=7.2 Hz, 1H), 6.74 (d, J=7.6 Hz, 1H), 6.68 (s,1H), 4.88 (d, J=6.4 Hz, 1H), 3.80-3.78 (m, 4H), 3.37-3.24 (m, 4H),2.80-2.68 (m, 3H), 2.51-2.34 (m, 4H), 1.38 (d, J=6.0 Hz, 3H), 1.28 (d,J=6.4 Hz, 3H). LCMS: (Method A) 394.2 (M+H), Rt 2.0 min, 98.9% (Max).HPLC: (Method A), Rt 2.5 min, 98.7% (Max). Chiral SFC: (Method C), Rt 1.2.2 min, 49.8% and Rt 2. 2.8 min, 49.4%.

Examples 16 and 17:N-(5-(4-((R)-1-((S)-2-methyl-2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamideandN-(5-(4-((S)-1-((S)-2-methyl-2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

The enantiomers of this racemic example 14 was separated by SFC; mobilephase: 0.5% isopropyl amine in methanol; column: Chiracel OD-H (MethodB), the first eluting fraction was concentrated to afford example 16 andsecond eluting fraction was concentrated to afford example 17.

Analysis of first eluting fraction (example 16): Yield: 35% (35 mg, offwhite solid). ¹H NMR (400 MHz, DMSO-d₆): δ 12.02 (s, 1H), 7.11 (d, J=7.6Hz, 1H), 6.64 (d, J=7.6 Hz, 1H), 6.67 (s, 1H), 4.89 (q, J=7.2 Hz, 1H),3.38-3.34 (m, 5H), 3.30-3.25 (m, 1H), 2.80-2.30 (m, 1H), 2.43-2.41 (m,4H), 2.10 (s, 3H), 1.38 (d, J=6.4 Hz, 3H), 1.28 (d, J=6.4 Hz, 3H). LCMS:(Method A) 388.1 (M+H), Rt 2.1 min, 99.1% (Max). HPLC: (Method A) Rt.2.6 min, 96.3% (Max). Chiral SFC: (Method B) Rt. 3.9 min, 99.1% (Max).

Analysis of second eluting fraction (example 17): Yield: 42% (42 mg, offwhite solid). ¹H NMR (400 MHz, DMSO-d₆): δ 12.02 (s, 1H), 7.12 (d, J=7.2Hz, 1H), 6.75 (d, J=7.6 Hz, 1H), 6.67 (s, 1H), 4.89 (q, J=8.0 Hz, 1H),3.36-3.33 (m, 6H), 2.80-2.75 (m, 1H), 2.51-2.40 (m, 4H), 2.10 (s, 3H),1.39 (d, J=6.0 Hz, 3H), 1.28 (d, J=6.4 Hz, 3H). LCMS: (Method A) 388.1(M+H), Rt 2.1 min 97.5% (Max). HPLC: (Method A) Rt. 2.6 min, 96.3%(Max). Chiral SFC: (Method B) Rt 4.5 min, 100% (Max).

Example 18:2-(4-((S)-1-((S)-2-methyl-2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneor2-(4-((R)-1-((S)-2-methyl-2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one

The enantiomers of example 15 were separated by SFC; mobile phase: 20 mMammonia in methanol, column: Chiracel OJ-H (Method C). The first elutingeluting fraction was concentrated to afford example 18.

Analysis of first eluting fraction (example 18): Yield: 35% (62 mg, offwhite solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.58 (s, 1H), 7.70 (s, 1H),7.11 (d, J=7.6 Hz, 1H), 6.75 (d, J=7.6 Hz, 1H), 6.68 (s, 1H), 4.88 (d,J=6.8 Hz, 1H), 3.85-3.75 (m, 4H), 3.36-3.23 (m, 3H), 3.26 (d, J=5.6 Hz,1H), 2.80-2.71 (m, 3H), 2.42-2.33 (m, 4H), 1.38 (d, J=6.0 Hz, 3H), 1.28(d, J=6.4 Hz, 3H). LCMS: (Method A) 394.2 (M+H), Rt 2.0 min, 99.6%(Max). HPLC: (Method A), Rt 2.6 min, 98.7% (Max). Chiral SFC: (Method C)Rt 2.0 min, 100% (max).

Analysis of second eluting fraction (example 18): Yield: 38% (68 mg, offwhite solid). ¹H NMR: (400 MHz, DMSO-d₆): δ 8.58 (s, 1H), 7.70 (s, 1H),7.11 (d, J=7.6 Hz, 1H), 6.75 (dd, J=7.6, 1.2 Hz, 1H), 6.68 (s, 1H), 4.85(d, J=6.8 Hz, 1H), 3.85-3.75 (m, 4H), 3.39-3.34 (m, 3H), 3.30-3.24 (m,1H), 2.80-2.75 (m, 3H), 2.42-2.34 (m, 4H), 1.38 (d, J=6.0 Hz, 3H), 1.28(d, J=6.8 Hz, 3H). LCMS: (Method A) 394.2 (M+H), Rt 2.0 min, 99.3%(Max). HPLC: (Method A), Rt 2.6 min, 98.5% (Max). Chiral SFC: (MethodC), Rt 2.5 min, 100% (max).

Example 19:2-(4-(1-((R)-2-methyl-2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-5-(methylsulfonyl)pyrimidine

Step 1: 2-chloro-5-(methylsulfonyl)pyrimidine

To a stirred solution of 2-chloro-5-(methylthio)pyrimidine (synthesisdescribed in intermediate 8, step 1) (800 mg, 5.0 mmol, Int) in DCM (30mL) cool to 0° C., m-CPBA (2.58 g, 15.0 mmol) was added, stirred thereaction mixture at rt for 3 h. The reaction mixture was evaporatedunder vacuum and to the resulting crude water (5 mL) was added. Theresulting compound was extracted with EtOAc (50×2 mL) and the combinedorganic layer was dried over anhydrous sodium sulfate and concentrated.The crude product was purified by column chromatography using eluentHexane:EtOAc (26%). Yield: 84.21% (3.2 g, yellow gummy). ¹H NMR: 400MHz, DMSO-d6: δ 9.25 (s, 2H), 3.43 (s, 3H). HPLC: (Method A), Rt. 1.48min, 93.30% (Max).

Step 2:2-(4-(1-((R)-2-methyl-2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-5-(methylsulfonyl)pyrimidine

To a stirred solution of intermediate 9 (0.3 g, 0.94 mmol) in ACN (3mL), 2-chloro-5-(methylsulfonyl)pyrimidine (0.2 g, 1.03 mmol) followedby TEA (0.53 mL, 3.75 mmol) were added at RT and the reaction mixturewas stirred at RT for 2 h. Completion of the reaction was monitored byTLC, then the reaction mixture was evaporated at 50° C. under vacuum. Tothe resulting mixture, water (2 mL) was added and the aqueous layer wasextracted with EtOAc (2×15 mL). The combined organic layer was washedwith brine solution (20 mL), dried over anhydrous Na₂SO₄ andconcentrated under vacuum. The resulting crude material was purified byflash chromatography (silica gel: 230-400 mesh, eluent: 4% methanol inDCM) to afford the title compound. Yield: 29% (111 mg, pale yellowsolid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.68 (s, 2H), 7.11 (d, J=7.6 Hz,1H), 6.75 (d, J=7.6 Hz, 1H), 6.68 (s, 1H), 4.91-4.86 (m, 1H), 3.85-3.83(m, 4H), 3.40-3.33 (m, 1H), 3.30-3.24 (m, 1H), 3.21 (s, 3H), 2.77-2.68(m, 1H), 2.56-2.33 (m, 4H), 1.38 (q, J=2.8 Hz, 3H), 1.28 (d, J=6.4 Hz,3H). LCMS: (Method A) 403.2 (M+H), Rt. 2.1 min, 98.6% (Max). HPLC:(Method A) Rt 2.9 min, 99.4% (Max).

Example 20:imino(methyl)(2-(4-(1-((R)-2-methyl-2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)-λ⁶-sulfanone

Step 1:2,2,2-trifluoro-N-(methyl(2-(4-(1-((R)-2-methyl-2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl) pyrimidin-5-yl) (oxo)-λ⁶-sulfanylidene)acetamide

To a stirred solution of intermediate 9 (0.3 g, 0.94 mmol) in ACN (3.0mL), TEA (0.53 mL, 3.75 mmol) and intermediate 8 (0.3 g, 1.03 mmol) wereadded at RT and the reaction mixture was stirred at RT for 2 h.Completion of the reaction was monitored by TLC, then the reactionmixture was evaporated at 50° C. under vacuum. To the resulting mixture,water (2 mL) was added and the aqueous layer was extracted with EtOAc(2×15 mL). The combined organic layer was washed with brine solution (20mL), dried over anhydrous Na₂SO₄ and concentrated under vacuum. Theresulting crude material was purified by flash chromatography (silicagel: 230-400 mesh, eluent: 25% EtOAc in pet-ether) to afford the titlecompound. Yield: 66% (0.31 g, pale yellow solid). ¹H NMR (400 MHz,DMSO-d₆): δ 8.68 (s, 2H), 7.11 (d, J=7.6 Hz, 1H), 6.80-6.76 (m, 2H),4.95 (q, J=7.2 Hz, 1H), 4.92-4.11 (m, 1H), 3.98-3.97 (m, 4H), 3.47 (s,3H), 3.34-3.28 (m, 1H), 2.85-2.79 (m, 1H), 2.55-2.54 (m, 4H), 1.54 (d,J=7.20 Hz, 3H), 1.49 (d, J=6.4 Hz, 3H). LCMS: (Method A) 402.1 (M+H), Rt2.5 min, 97.1% (Max).

Step 2:Imino(methyl)(2-(4-(1-((R)-2-methyl-2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)-λ⁶-sulfanone

To a stirred solution of2,2,2-trifluoro-N-(methyl(2-(4-(1-((R)-2-methyl-2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)(oxo)-λ⁶-sulfanylidene)acetamide(0.31 g, 0.61 mmol) in methanol (6.1 mL, 20 V), K₂CO₃ (170 mg, 1.22mmol) was added and the reaction mixture was stirred for 20 min.Completion of the reaction was monitored by TLC, then after 20 min, thereaction mixture was filtered through celite and the filtrate wasconcentrated under vacuum. To the resulting mixture, water (2 mL) wasadded and the aqueous layer was extracted with EtOAc (2×10 mL). Thecombined organic layer was washed with brine solution (10 mL), driedover anhydrous Na₂SO₄ and concentrated under vacuum. The resulting crudematerial was purified by flash chromatography (Biotage Isolera,gradient: 1-4% methanol in DCM) to afford the title compound. Yield: 19%(74 mg, off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.66 (s, 2H),7.11 (d, J=7.6 Hz, 1H), 6.75 (d, J=7.2 Hz, 1H), 6.68 (s, 1H), 4.89-4.86(m, 1H), 4.25 (s, 1H), 3.83-3.81 (m, 4H), 3.39-3.34 (m, 1H), 3.30-3.24(m, 1H), 3.08 (s, 3H), 2.77-2.68 (m, 1H), 2.44-2.34 (m, 4H), 1.38 (q,J=6.2 Hz, 3H), 1.28 (d, J=6.4 Hz, 3H). LCMS: (Method A) 402.2 (M+H), Rt1.9 min, 99.0% (Max). HPLC: (Method A) Rt 2.3 min, 97.9% (Max).

Example 21:5-(4-(1-((R)-2-methyl-2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2(3H)-oneStep 1: tert-butyl 4-(hydrazinecarbonothioyl)piperazine-1-carboxylate

To a stirred solution of tert-butyl piperazine-1-carboxylate (5.0 g,26.845 mmol) in THF (50 mL), TEA (11.31 mL, 80.536 mmol) andthiocarbonyldiimidazole (9.57 g, 53.69 mmol) were added at RT and thereaction mixture was stirred for 2 h at RT. After 2 h, hydrazine hydrate(4.03 mL, 80.54 mmol) was added to the reaction mixture and stirred for2 h at RT. Completion of the reaction was monitored by TLC, then water(50 mL) was added to the resulting mixture and the aqueous layer wasextracted with EtOAc (2×25 mL). The combined organic layer was washedwith brine solution (20 mL), dried over anhydrous Na₂SO₄ andconcentrated under vacuum. The resulting crude material was forwarded assuch to the next step without any further purification. Yield: 92% (4.5g, off white solid.). ¹H NMR (400 MHz, DMSO-d₆): δ 9.12 (s, 1H), 4.74(bs, 2H), 3.71 (d, J=4.1 Hz, 4H), 2.80-2.78 (m, 4H) 1.41 (s, 9H). LCMS:(Method A) 261.0 (M+H), Rt. 2.0 min, 95.6% (Max).

Step 2: tert-butyl 4-(5-oxo-4,5-dihydro-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate

To the stirred solution of tert-butyl 4-(hydrazinecarbonothioyl)piperazine-1-carboxylate (4.5 g, 13.46 mmol) in DCM (35 mL), TEA (6.60mL, 40.39 mmol) and carbonyldiimidazole (8.3 g, 40.39 mmol) were addedat RT for 4 h. Completion of the reaction was monitored by TLC, thenwater (25 mL) was added to the resulting mixture and the aqueous layerwas extracted with EtOAc (2×25 mL). The combined organic layer waswashed with brine solution (25 mL), dried over anhydrous Na₂SO₄ andconcentrated under vacuum. The resulting crude material was purified byflash chromatography (silica gel: 230-400 mesh, eluent: 1-2% methanol inDCM) to afford the title compound. Yield: 58% (2.8 g, off white solid).¹H NMR (400 MHz, DMSO-d₆): δ 11.79 (s, 1H), 3.38-3.36 (m, 4H), 3.18-3.16(m, 4H), 1.41 (s, 9H). LCMS: (Method A) 231.0 (M-t-butyl), Rt. 2.4 min,99.9% (Max).

Step 3: 5-(piperazin-1-yl)-1, 3, 4-thiadiazol-2(3H)-one hydrochloride

To a stirred solution of tert-butyl 4-(hydrazinecarbonothioyl)piperazine-1-carboxylate (2.8 g, 5.069 mmol) in dry 1,4-dioxane (10 mL)at 0° C., HCl solution in dioxane (20 mL, 4M) was added dropwise and thereaction mixture was stirred for 4 h at RT. Completion of the reactionwas monitored by TLC, then the reaction mixture was evaporated undervacuum to afford the tittle compound. Yield: 86% (1.81 g, off whitesolid). ¹H NMR (400 MHz, DMSO-d₆): δ 11.96 (s, 1H), 9.51 (s, 2H), 3.45(t, J=4.8 Hz, 4H), 3.16 (bs, 4H). LCMS: (Method A) 187.1 (M+H), Rt. 0.5min, 90.7% (Max).

Step 4: 5-(4-(1-((R)-2-methyl-2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2(3H)-one

To a stirred solution of 5-(piperazin-1-yl)-1,3,4-thiadiazol-2(3H)-onedihydrochloride (0.51 g, 1.95 mmol)) in dry DMF (3.5 mL), TEA (1.0 mL,7.11 mmol) and intermediate 4 (350 mg, 1.77 mmol) were added at Rt andthe reaction mixture was heated at 80° C. overnight. Completion of thereaction was monitored by TLC, then the reaction mixture was evaporatedat 55° C. under vacuum. To the resulting mixture, water (2 mL) was addedand the aqueous layer was extracted with EtOAc (3×10 mL). The combinedorganic layer was washed with brine solution (10 mL), dried overanhydrous Na₂SO₄ and concentrated under vacuum. The resulting crudematerial was purified by flash chromatography (Biotage Isolera, eluent:4-5% methanol in DCM) to afford the title compound. Yield: 30% (184 mg,pale yellow solid). ¹H NMR (400 MHz, DMSO-d₆): δ 11.70 (s, 1H), 7.11 (d,J=7.6 Hz, 1H), 6.73 (d, J=7.6 Hz, 1H), 6.66 (s, 1H), 4.91-4.85 (m, 1H),3.39-3.33 (m, 1H), 3.30-3.24 (m, 1H), 3.17-3.12 (m, 4H), 2.77-2.68 (m,1H), 2.48-2.35 (m, 4H), 1.38 (d, J=6.4 Hz, 3H), 1.26 (d, J=6.4 Hz, 3H).LCMS: (Method A) 347.1 (M+H), Rt 2.0 min, 96.2% (Max). HPLC: (Method A)Rt 2.5 min, 94.8% (Max).

Example B01: Human O-GlcNAcase Enzyme Inhibition Assay

5 μl of the appropriate concentration of a solution of inhibitor inMcllvaine's Buffer (pH 6.5) in 2% DMSO (for a dose response curvecalculation) is added into each well of a 384-well plate (Greiner,781900). Then, 20 nM of His-Tagged hOGA and 10 μM of FL-GlcNAc(Fluorescein mono-beta-D-(2-deoxy-2-N-acetyl) glucopyranoside; MarkerGene Technologies Inc, M1485) were added to the 384-well plate for afinal volume of 20 μl. After incubation for 60 min at room temperature,the reaction was terminated by the addition of 10 μL of stop buffer (200mM glycine, pH 10.75). The level of fluorescence (λ_(exc) 485 nm;(λ_(emm) 520 nm) was read on a PHERAstar machine. The amount offluorescence measured was plotted against the concentration of inhibitorto produce a sigmoidal dose response curve to calculate an IC₅₀. Allindividual data was corrected by subtraction of the background (Thiamet3 uM=100% inhibition) whilst 0.5% DMSO was considered as the controlvalue (no inhibition).

Example B02: Pharmacodynamic Model: Total Protein O-GlcNAcylationImmunoassay (RL2 mAb, Meso Scale Electrochemiluminescence (ECL) Assay)

The test compound was administered orally to C57BL/6J mice. At definedtime intervals after compound administration, typically a time rangingbetween 2 and 48 hours, preferably between 4 and 24 hours, mice weresacrificed by decapitation for blood collection and forebraindissection. Right brain hemispheres were placed in 2 ml Precellys tubes,snap frozen in dry ice and stored at -80° C. Left hemispheres wereplaced in 2 ml Eppendorf tubes, snap frozen in dry ice and stored at-80° C. until further processing. Blood samples were collected inSarstedt tubes containing 35 IU of Heparin and kept at 4° C. Aftercentrifugation for 10 min at 3800 xg, 4° C., 50 μL of plasma from eachsample was transferred to a 1.5 ml Eppendorf tube and stored at −80° C.

For the preparation of soluble brain protein for the immunoassay thehemispheres were homogenized in ice-cold Cytobuster reagent (71009—MerckMillipore) buffer with protease inhibitor cocktail. After centrifugationfor 15 min at 17000 xg at 4° C. the supernatants were transferred intopolycarbonate tubes (1 ml). The supernatants were cleared bycentrifugation for 1 h. at 100000 xg, 4° C., and the proteinconcentrations were determined by using the BCA kit (23227—Pierce,Rockford, Ill.) according to the manufacturer's instructions.

Total Protein O-GlcNAcylation Immunoassay:

Samples were randomised and 120 μg/ml (25 μl/well) of soluble brainprotein was directly coated on a Multi-array 96-well high bind plate(L15XB-3 High bind—Meso Scale Discovery) overnight at 4° C. Afterwashing (3× with PBS-T buffer), the plate was blocked with MSD blocker Asolution for 1 h. at room temperature (RT) under agitation. Afterwashing (3× with PBS-T buffer), the plate was incubated with 0.1 μg/mlof a mouse monoclonal antibody directed against O-GlcNAc moieties (RL2;MA1-072—Thermo Scientific) for 1 h. at RT under agitation. For the ECLassay, after washing (3× with PBS-T buffer), 1 μg/ml of a SULFO-TAG™labeled anti-mouse secondary antibody (Meso Scale Discovery) was addedand the plate was incubated for 1 h. at RT under agitation and protectedfrom light. After washing (3× with PBS-T buffer), 150 μl/well of 1× ReadBuffer T was added to the plates before reading on a Sector Imager 6000(Meso Scale Discovery).

Example B03: Pharmaceutical Preparations

(A) Injection vials: A solution of 100 g of an active ingredientaccording to the invention and 5 g of disodium hydrogen phosphate in 3 lof bi-distilled water was adjusted to pH 6.5 using 2 N hydrochloricacid, sterile filtered, transferred into injection vials, lyophilizedunder sterile conditions and sealed under sterile conditions. Eachinjection vial contained 5 mg of active ingredient.

(B) Suppositories: A mixture of 20 g of an active ingredient accordingto the invention was melted with 100 g of soy lecithin and 1400 g ofcocoa butter, poured into moulds and allowed to cool. Each suppositorycontained 20 mg of active ingredient.

(C) Solution: A solution was prepared from 1 g of an active ingredientaccording to the invention, 9.38 g of NaH₂PO₄.2H₂O, 28.48 g ofNa₂HPO₄.12H₂O and 0.1 g of benzalkonium chloride in 940 ml ofbi-distilled water. The pH was adjusted to 6.8, and the solution wasmade up to 1 l and sterilized by irradiation. This solution could beused in the form of eye drops.

(D) Ointment: 500 mg of an active ingredient according to the inventionwere mixed with 99.5 g of Vaseline under aseptic conditions.

(E) Tablets: A mixture of 1 kg of an active ingredient according to theinvention, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and0.1 kg of magnesium stearate was pressed to give tablets in aconventional manner in such a way that each tablet contained 10 mg ofactive ingredient.

(F) Coated tablets: Tablets were pressed analogously to EXAMPLE E andsubsequently coated in a conventional manner with a coating of sucrose,potato starch, talc, tragacanth and dye.

(G) Capsules: 2 kg of an active ingredient according to the inventionwere introduced into hard gelatin capsules in a conventional manner insuch a way that each capsule contained 20 mg of the active ingredient.

(H) Ampoules: A solution of 1 kg of an active ingredient according tothe invention in 60 l of bi-distilled water was sterile filtered,transferred into ampoules, lyophilized under sterile conditions andsealed under sterile conditions. Each ampoule contained 10 mg of activeingredient.

(I) Inhalation spray: 14 g of an active ingredient according to theinvention were dissolved in 10 I1 of isotonic NaCl solution, and thesolution was transferred into commercially available spray containerswith a pump mechanism. The solution could be sprayed into the mouth ornose. One spray shot (about 0.1 ml) corresponded to a dose of about 0.14mg.

Example B04: Protein Binding in Mice Plasma Using Rapid EquilibriumDialysis

Materials

-   -   CD1 Mice Plasma: pooled male, K2-EDTA (MSEPLEDTA2,        Bioreclammation, USA    -   Phosphate Buffered Saline (1×PBS), pH 7.4, 100 mM (Sigma, Cat        No. P4417)    -   RED inserts (Pierce, Cat No. 9006, 8 kDa MWCO)    -   Sample Analysis: LC-MS/MS

Methods

Preparation of DMSO Stock Solution

From 20 mM DMSO stock solutions of reference and test compounds, 1 mMDMSO intermediate working solutions are prepared. From 1 mM intermediateworking solutions, 100 μM DMSO working solutions are prepared.

Sample Preparation Procedure:

Selected plasma is brought from −20° C. to 37° C. using water bathbefore its use. Test solution is prepared by adding the DMSO workingsolution of the reference or test compound (2 μL; 100 μM) to theselected plasma (198 μL). Spiked plasma (200 μl) is transferred tosample compartment of RED insert placed in the teflon plate. 350 μl of1×PBS is added in the buffer compartment of RED insert. The teflon plateis covered with sealing mat and agitated at 37° C. for 5 hours at 500RPM in a Thermomixer. After incubation time, an aliquot of plasma (50μl) from sample compartment is mixed with blank 1×PBS (50 μl).Similarly, an aliquot of buffer (50 μl) from buffer compartment is mixedwith blank plasma (50 μl). Quenching solution (200 μL, acetonitrilecontaining internal standard tolbutamide (0.5 μg/mL)) is added and theresulting solutions are mixed using a vortex mixer and centrifuged(Eppendorf 5415, 13792 g). Supernatants are analyzed using a MassSpectrometer. The sample (supernatant fraction, 5 μL) is injected intothe LC-MS/MS instrument.

Chromatographic Conditions:

LC-MS/MS: API 4000 LC-MS/MS

Software: Analyst Version 1.6.1

Column Phenomenex Synergy 30*4.6*5μ

Column Oven: 40° C.

Mode: ESI Positive

Injection volume: 5 μl

Flow Rate: 1000 μL/mL

Buffer: 0.1% Formic acid in Water

Method: Isocratic Method/Gradient

Composition: A) 0.1% Formic acid in Water

-   -   B) 0.1% Formic acid in Methanol

Mobile Mobile Time (Sec) Flow (μL) Phase A Phase B 0.01 1000 10 90 0.41000 10 90 0.8 1000 90 10 1.5 1000 90 10 1.8 1000 10 90 2.5 1000 10 90

Results Calculation

After the concentration of free drug and total drug has been determinedby LCMS/MS, percent plasma protein binding can be calculated as follows:

${\% \mspace{14mu} {fraction}\mspace{14mu} {unbound}} = {\frac{{Drug}\mspace{14mu} {concentration}\mspace{14mu} {in}\mspace{14mu} {buffer}\mspace{14mu} {after}\mspace{14mu} 5\mspace{14mu} {hours}}{{Drug}\mspace{14mu} {concentration}\mspace{14mu} {in}\mspace{14mu} {plasma}\mspace{14mu} {after}\mspace{14mu} 5\mspace{14mu} {hours}} \times 100}$

Following this protocol, % fraction unbound in plasma from differentspecies can be also measured.

Example B05: Determination of In Vitro Intrinsic Clearance (Cl_(int)-InVitro) with Mouse, Rat and Human Liver Microsomes

In this assay, test compounds are incubated with liver microsomes frommouse, rat and human, and rate of disappearance of drug is determinedusing LC-MS/MS. Conditions used in the assay are summarized below:

Materials

-   -   CD-1 Mice liver microsomes, pooled male (Life Technologies, Cat        No. MSMC-PL) (20 mg/ml)    -   SD Rat liver microsomes, pooled male (Life Technologies, Cat No.        RTMCL-PL) (20 mg/ml)    -   Human liver microsomes, pooled mixed gender (Life Technologies,        Cat No. HMMC-PL) (20 mg/ml)    -   NADPH (SRL Mumbai, Cat No. 99197)    -   Verapamil (Sigma, Cat No. V4629)    -   Atenolol (Sigma, Cat No. A7655)    -   Tolbutamide (Sigma Cat. No. T0891)    -   Assay buffer: 50 mM potassium phosphate buffer, pH 7.4    -   Test & reference compounds: DMSO stock solutions (10 mM        concentration) are prepared and stored at room temperature. An        intermediate 1 mM solution of test or reference compounds is        prepared by mixing 10 μL of 10 mM DMSO stock with 90 μL of DMSO.        The contents are mixed vigorously in a vortex mixer.

Methods

Preparation of Working Solutions of Test and Reference Compounds:

Working solution (100 μM concentration) is prepared by mixing 10 μL of 1mM DMSO solution of test or reference compounds with 90 μL of assaybuffer. The mixture is mixed vigorously in a vortex mixer. Thisresulting solution is containing 10% of DMSO. For the metabolicstability assay, 10 μL of this 100 μM working solution is added to afinal assay volume of 1 mL, yielding final test concentration of 1 μMand DMSO concentration of 0.1%.

Metabolic Stability Assay

Metabolic stability assay is done in a final volume of 1 ml in 50 mMassay buffer, potassium phosphate buffer, pH 7.4. Assay is carried outin duplicates (n=2). A mixture containing 955 μL of assay buffer, 25 μLof liver microsomes and 10 μL of 100 μM test compound solution ispre-incubated for 10 minutes in a water-bath maintained at 37° C. Afterpre-incubation, reaction is started by adding 10 μL of 100 mM NADPHsolution. The solution is mixed and incubated at 37° C. in a water-bath.The final concentration of the different components in the assay is:DMSO 0.1%, test compound 1 μM, liver microsome protein 0.5 mg/ml andNADPH 1 mM.

Aliquots (100 μL) are taken at various time-points (0, 5, 15, 30 and 45minutes) and quenched with 100 μL of acetonitrile containing tolbutamide(500 ng/mL) as internal standard. Samples are mixed using a vortex mixerand centrifuged at 4000 rpm for 10 minutes (Eppendorf 5810R, 3000 g).The supernatants (5 μL) are transferred to 96 well plates and submittedfor LC-MS/MS analysis.

Separate incubations in the same assay mixture, but in the absence ofNADPH, are run in parallel as control for compound stability. Thiscontrol assay is carried out in duplicates (n=2). After pre-incubation,addition of NADPH is omitted and replaced with 10 μL of assay buffer.The final assay volume is 1 mL and aliquots (100 μL) are withdrawn andprocessed for analysis as described for metabolic stability assay.

LC-MS/MS Conditions (Generic Method)

LC-MS/MS: API Sciex 4000 with Nexera™ UHPLC

Software: Analyst Version 1.6.1

Column: Phenomenex kinetex C18 50×3.0 mm, 2.6p

Column Oven: 40° C.

Mode: ESI Positive

Injection volume: 5 μl

Flow Rate: 1000 μL/mL

Buffer: 0.1% Formic acid in Water

Method: Isocratic Method/Gradient

Composition: A) 0.1% Formic acid in Water

-   -   B) 0.1% Formic acid in Methanol

Mobile Mobile Time (Sec) Flow (μL) Phase A Phase B 0.01 1000 10 90 0.41000 10 90 1 1000 90 10 1.5 1000 90 10 1.8 1000 10 90 3 1000 10 90

Results Calculation

From LC-MS/MS data, amount of drug remaining at different time pointswas determined (% PCR). The logarithm of % PCR was plotted against timeto get the slope value. From the slope value, in vitro T_(1/2) wasdetermined. In vitro intrinsic clearance (Cl_(int)) was calculated usingthe following formulae:

${CL}_{int} = {{\frac{0.693}{{In}\mspace{14mu} {vitro}\mspace{14mu} t_{1/2}} \times \frac{{Volume}\mspace{14mu} {of}\mspace{14mu} {incubation}}{{mg}\mspace{14mu} {of}\mspace{14mu} {microsomal}\mspace{14mu} {protein}}\mspace{14mu} {In}\mspace{14mu} {vitro}\mspace{14mu} t_{1/2}} = \frac{0.693}{K_{el}}}$

Where K_(el) is Elimination Constant (slope)

Methods for treating the diseases mentioned in this specification, suchas tauopathy, by administering one or more of the compounds of thepresent invention to a patient in need thereof are also object of thisinvention.

If chemical bonds in the structures above are drawn as follows:

they indicate a defined, i.e. R or S, stereochemistry at at least one ofthe atoms to which they are attached to.

This is exemplified below, wherein the structure

is representing only one of the two possible diastereoisomers,

i.e. a single individual chemical structure as opposed to a mixture ofdiastereoisomers.

1. A compound of formula (I)

wherein R is straight chain or branched alkyl having 1 to 6 carbonatoms, wherein 1 to 5 hydrogen atoms may be replaced by Hal or OH; W isCH or N; X is N or CR′″; R′, R″ denote each independently H, Hal orstraight chain or branched alkyl having 1 to 12 carbon atoms, wherein atleast one of R′ and R″ is different from H; R′″ denotes H, Hal, NR³R⁴,CHR³R⁴, OR³, CN or a straight chain or branched alkyl having 1 to 12carbon atoms, wherein 1 to 3 CH₂-groups may be replaced by a groupselected from O, NR³, S, SO, SO₂, S(O)(NR^(3′)), N(SO)R^(3′), CO, COO,OCO, CONR³, NR³CO,

 and wherein 1 to 5 hydrogen atoms may be replaced by Hal, NR³R⁴ or NO₂or by one of the following groups:

 or R′″ denotes one of the following groups:

R³, R⁴ denote each independently H or a straight chain or branched alkylgroup having 1 to 12 carbon atoms; Q denotes one of the followinggroups:

Y is N or CR′″; Z¹ is S, O, NR³; Z², Z³ independently denote CR⁵ or N;Z⁴ is N, CH, CON, COCH; Z⁵ is NR⁸, CHR⁵, S(O)(NR³′), N(SO)R^(3′),

Z⁶ is CH₂, CO, SO₂, S(O)(NR^(3′)), N(SO)R^(3′),

Z⁷ is C(R^(3′))₂, S, O, NR^(3′); s denotes 0 or 1; T is N, CH or CR⁷;R^(3′) denotes H or a straight chain or branched alkyl group having 1 to12 carbon atoms, wherein 1 to 3 CH₂-groups may be replaced by a groupselected from SO₂, CO, O and wherein 1 to 5 hydrogen atoms may bereplaced by Hal; R⁵, R⁶, R⁷ independently denote H, Hal, NR³R⁴, NO₂ or astraight chain or branched alkyl having 1 to 12 carbon atoms, wherein 1to 3 CH₂-groups may be replaced by a group selected from O, NR³, S, SO,SO₂, S(O)(NR^(3′)), N(SO)R^(3′), CO, COO, OCO, CONR³, NR³CO

 and wherein 1 to 5 hydrogen atoms may be replaced by Hal, NR³R⁴, NO₂,OR³, Het, Ar, Cyc, or by one of the following groups:

 or R⁵, R⁶, R⁷ denote Ar, Het or Cyc or one of the following groups:

R⁸ denotes H or straight chain or branched alkyl having 1 to 12 carbonatoms, wherein 1 to 3 CH₂-groups may be replaced by a group selectedfrom SO, SO₂, S(O)(NR^(3′)), N(SO)R^(3′), CO, COO, OCO, CONR³, NR³CO,and

and further wherein 1 to 5 hydrogen atoms may be replaced by CN, OR³,SR³, Hal, NR³R⁴, NO₂ or by one of the following groups:

 or R⁸ denote one of the following groups:

Hal denotes F, Cl, Br or I; Het denotes a saturated, unsaturated oraromatic ring, being monocyclic or bicyclic or fused-bicyclic and having3- to 8-members and containing 1 to 4 heteroatoms selected from N, O andS, which may be substituted by 1 to 3 substituents selected from R⁵, Haland OR³; Ar denotes a 6-membered carbocyclic aromatic ring or a fused ornon-fused bicylic aromatic ring system, which is optionally substitutedby 1 to 3 substituents independently selected from R⁵, OR³ and Hal; Cycdenotes a saturated or an unsaturated carbocyclic ring having from 3 to8 carbon atoms which is optionally substituted by 1 to 3 substituentsindependently selected from R⁵ or Hal or OH; m and n denoteindependently from one another 0, 1, 2 or 3, t and q denoteindependently from one another 0, 1, 2 or 3, with t+q>1; andpharmaceutically usable derivatives, solvates, salts, prodrugs,tautomers, enantiomers, racemates and stereoisomers thereof, includingmixtures thereof in all ratios and compounds of formula I, wherein oneor more H atoms are replaced by D (deuterium).
 2. A compound chosen fromthe group consisting of formula Ia and Ib:

wherein R, R′, R″, X, W, Q, n and m have the meaning given in claim 1.3. A mixture comprising compounds Ia and Ib according to claim 2, havingidentical groups R, R′, R″, X, W, Q, n and m in equal or unequalamounts.
 4. A compound of formula I according to claim 1, wherein R ismethyl and/or W is N.
 5. A compound of formula I according to claim 1,wherein the groups X denote both simultaneously CH.
 6. A compound offormula I according to claim 1, wherein Q denotes one of the followinggroups:

wherein T, Y, Z⁵, Z⁶, R′″, R⁵, R⁶, R⁷ and R⁸ have the meaning given inclaim
 1. 7. A compound of formula I according to claim 1 to claim 6,wherein R⁵, R⁶, R⁷ are independently selected from H, SO₂CH₃, SO₂CH₂CH₃,SO₂CH₂CH₂OH, SO₂CH₂CH₂OCH₃, S(O)(NR^(3′))CH₃, S(O)(NR^(3′))CH₂CH₃,S(O)(NR^(3′))CH₂CH₂OH, S(O)(NR^(3′))CH₂CH₂OCH₃, N(SO)R^(3′)CH₃,N(SO)R^(3′)CH₂CH₃, N(SO)R^(3′)CH₂CH₂OH, N(SO)R^(3′)CH₂CH₂OCH₃, Hal,NR³R⁴, NO₂, phenyl, 2-, 3- or 4-hydroxy or methoxyphenyl, alkyl, alkoxy(Oalkyl), hydroxyalkylen, alkoxyalkylen, COOH, COOalkyl, CONHalkyl,CONH₂, CON(CH₃)₂, NHCOalkyl, NHCH₂CH₃, NHCH₂CH₂CH₃, NHCOCH₂CH₂OH,CO—N-morpholinyl, CON(CH₃)CH₂CH₂N(CH₃)₂, CO-1-piperidinyl,CO-4-hydroxy-1-piperidinyl, CO-1-piperazinyl, CO-4-methyl-1-piperazinyl,CH₂—N— morpholinyl, CH₂N(H)COCH₃, CH₂N(CH₃)COCH₃, CH₂NH₂, NH₂,CH(OH)CH₃, CH(OR³)CH₃ and a group

wherein t+q is 2 or 3, Z⁷, R³, R⁴ and R^(3′) have the meaning given inclaim
 1. 8. A compound of formula Ic

wherein R, R′, W, Q, n and m have the meaning given in claim
 1. 9. Acompound of formula I according to any one of claim 1 to claim 8,wherein m and n simultaneously denote
 1. 10. A compound according toclaim 1, selected from the following group: Configuration No Structurespecification 1

Racemic 2

Racemic 3

Racemic 4

Racemic 5

Racemic 6

Racemic 7

Racemic 8

Racemic 9

Synthesized from (R)-propane-1,2- diol 10

Synthesized from (R)-propane-1,2- diol 11

Chiral SFC Method A: 1st eluting compound 12

Chiral SFC Method A: 2nd eluting compound 13

Chiral SFC Method A: 1st eluting compound 14

Synthesized from (S)-propane-1,2- diol 15

Synthesized from (S)-propane-1,2- diol 16

Chiral SFC Method B: 1st eluting compound 17

Chiral SFC Method B: 2nd eluting compound 18

Chiral SFC Method C: 1st eluting compound 19

Synthesized from (R)-propane-1,2- diol 20

Synthesized from (R)-propane-1,2- diol 21

Synthesized from (R)-propane-1,2- diol

and/or and pharmaceutically usable derivatives, solvates, salts,tautomers, enantiomers, racemates and stereoisomers thereof, includingmixtures thereof in all ratios.
 11. A compound of formula (I) accordingto any one of claims 1 to 10 for use as a medicament.
 12. A compound offormula (I) according to any one of claims 1 to 10 and pharmaceuticallyusable derivatives, solvates, salts, tautomers, enantiomers, racematesand stereoisomers thereof, including mixtures thereof in all ratios foruse in a treatment of a condition selected from neurodegenerativediseases, diabetes, cancer, cardiovascular diseases and stroke.
 13. Acompound for use in a treatment of a condition according to claim 12,wherein the condition is selected from the group of one or moretauopathies and Alzheimer's disease, Dementia, Amyotrophic lateralsclerosis (ALS), Amyotrophic lateral sclerosis with cognitive impairment(ALSci), Argyrophilic grain disease, Behavioural variant frontomeporaldmenetia (BvFTD), Bluit disease, Chronic traumatic encephalopathy,Corticobasal degeneration (CBP), Dementia pugilistica, Diffuseneurofibrillary tangles with calcification, Down's syndrome, FamilialBritish dementia, Familial Danish dementia, Frontotemporal dementia withparkinsonism linked to chromosome 17 (FTDP-17), Frontotemporal lobardegeneration (FTLD), Ganglioglioma, Gangliocytoma,Gerstmann-Straussler-Scheinker disease, Globular glia tauopathy,Guadeloupean parkinsonism, Hallevorden-Spatz disease (neurodegenerationwith brain iron accumulation type 1), Lead encephalopathy,Lipofuscinosis, Meningioangiomatosis, Multiple system atrophy, Myotonicdystrophy, Niemann-Pick disease (type C), Pallido-ponto-nigraldegeneration, Parkinsonism-dementia complex of Guam, Pick's disease(PiD), Parkinson's disease dementia, Postencephalitic parkinsonism(PEP), Primary progressive aphasia, Prion diseases (includingCreutzfeldt-Jakob Disease (GJD), Progressive nonfluent aphasia, VariantCreutzfeldt-Jakob Disease (vCJD), Fatal Familial Insomnia, Kuru,Progressive supercortical gliosis, Progressive supranuclear palsy (PSP),Semantic dementia, Steele-Richardson-Olszewski syndrome, Subacutesclerosing panencephalitis, Tangle-only dementia, Tuberous sclerosis,Huntington's disease and Parkinson's disease, preferably one or moretauopathies and Alzheimer's disease.
 14. A method for treating atauopathy, wherein a compound defined in any one of claims 1 to 10 isadministered to a mammal in need of such treatment.
 15. A method forinhibiting a glycosidase, wherein a system expressing the glycosidase iscontacted with a compound as defined in any one of claims 1 to 10 underin-vitro conditions such that the glycosidase is inhibited.
 16. Apharmaceutical composition comprising as active ingredient a compoundaccording to any one of claims 1 to 10 together with pharmaceuticallytolerable adjuvants and/or excipients, optionally in combination withone or more further active ingredients.